RAF Inhibitors and Uses Thereof

ABSTRACT

The present invention provides imidazooxazole and imidazothiazole compounds and their synthesis. The compounds of the present invention are capable of inhibiting the activity of RAF kinase, such as B-RAF V600E . The compounds are useful for the treatment of cell proliferative disorders such as cancer.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/792,314, filed Apr. 17, 2006, the contents of which are incorporatedherein by reference in their entirety.

BACKGROUND OF THE INVENTION

There are three RAF isoforms in humans: A-RAF, B-RAF and C-RAF (Maraisand Marshall. Cancer Surv. 27:101-125 (1996)). These serine/threonineprotein kinases are components of a conserved signaling pathwaydownstream of the membrane-bound small G protein RAS, which is activatedby growth factors, hormones, and cytokines (Robinson and Cobb, Curr.Opin. Cell Biol. 9:180-186 (1997)). RAS stimulates RAF activation, whichthen leads to activation of the MEK kinase and subsequently the ERKkinase. Depending on the cellular context, this pathway mediates diversebiological functions such as cell growth, survival and differentiationpredominantly through the regulation of transcription, metabolism andcytoskeletal rearrangements.

The RAS-RAF signaling pathway has long been associated with humancancers because oncogenic mutations in the ras gene occur in at least15% of all human cancers (Davies, H. et al., Nature 417:949-954 (2002)),and the downstream kinase ERK is hyperactivated in 30% of cancers(Allen, et al., Semin. Oncol. 30:105-116 (2003)). However, for more thana decade, the RAF proteins had been considered to be important in canceronly because of their position downstream of RAS. This view was changedradically when activating mutations of B-RAF were found at a highfrequency in human cancer, implicating B-RAF as a critical initiator andpromoter of malignancy (Davies, H. et al., Nature 417:949-954 (2002)).

Activating mutations in the B-RAF protooncogene underlie 70% ofmelanomas, 50% of papillary thyroid cancers and 10% of colon cancers(Tuveson, et al., Cancer Cell 4:95 -98 (2003); and Xing,Endocrine-Related Cancer: 12:245-262 (2005). Approximately 90% of thesemutations occur as a single-nucleotide substitution that converts avaline to glutamate at amino acid 600 (V600E) in the kinase domain ofB-RAF. This mutation increases the basal kinase activity of B-RAF,resulting in the activation of the MEK and ERK proteins that ultimatelyleads to uncontrolled tumor cell growth. Significantly, B-RAF and RASmutations are usually mutually exclusive in the same tumor types,suggesting that these genes are on the same oncogenic signaling pathwayand that RAS acts to activate B-RAF in these tumors.

Recent studies have found that knockdown of mutant B-RAF by smallinterference RNA in human melanoma cells inhibits both MEK and ERKkinases, causing growth arrest and ultimately promoting apoptosis(Sharma, et al., Cancer Res. 65:2412-2421 (2005); and Wellbrock et al.,Cancer Res. 64:2338-2342 (2004)). In addition, data obtained from ashort-hairpin RNA xenograft models targeting mutant B-RAF have shownthat tumor regression resulting from B-RAF suppression is inducible,reversible, and tightly regulated (Hoeflich et al., Cancer Res.66:999-1006 (2006). Taken together, gain-of-function B-RAF signaling isstrongly associated with in vivo tumorigenicity, confirming B-RAF as animportant target for cancer therapeutics.

The references cited herein are not admitted to be prior art to theclaimed invention.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I orpharmaceutically acceptable salts thereof

wherein

X is O, S(O)_(p);

p is an integer from 0 to 2;

R₁ is halogen, —CN, —NO₂, —OH, —O—(C₁-C₈ substituted or unsubstitutedalkyl), —O—(C₁-C₈ fluoroalkyl), —(CH₂)₀₋₃—CO₂H, —(CH₂)₀₋₃—C(O)O-alkyl,-(C₁-C₈ substituted or unsubstituted alkyl), —(C₁-C₈ fluoroalkyl),—(C₃-C₈ cycloalkyl), —(C₃-C₈ fluorocycloalkyl), O-aryl(substituted orunsubstituted), —O-heteroaryl (substituted or unsubstituted), —NR₆R₇,—N₈—C(O)R₉, —NR₈—C(O)-fluoroalkyl, —NR₈—C(O)— aryl(substituted orunsubstituted), —(CH₂)₀₋₃—C(O)NR₆R₇, —NR₈SO₂R₉, —NR₉C(O)NR₆R₇,—NR₈C(S)NR₆R₇, —OSO₂NR₆R₇, —C(N—OH)NH₂, —C(N—OH)R₈, —CH₂OR₉,—OC(O)NR₆R₇, —SR₉, or —C(O)NR₈SO₂R₉;

R₂ is hydrogen, halogen, —CN, —NO₂, —OH, —O—(C₁-C₈ substituted orunsubstituted alkyl), —O—(C₁-C₈ fluoroalkyl), —(CH₂)₀₋₃—CO₂H,—(CH₂)₀₋₃—C(O)O-alkyl, —(C₁-C₈ substituted or unsubstituted alkyl),—(C₁-C₈ fluoroalkyl), —(C₃-C₈ cycloalkyl), —(C₃-C₈ fluorocycloalkyl),O-aryl(substituted or unsubstituted), —O-heteroaryl (substituted orunsubstituted), —NR₆R₇, —NR₉—C(O)R₉, —NR₉—C(O)-fluoroalkyl,—NR₈—C(O)-aryl (substituted or unsubstituted), —(CH₂)₀₋₃—C(O)NR₆R₇,—NR₈SO₂R₉, —NR₈C(O)NR₆R₇, —NR₈C(S)NR₆R₇, —OSO₂NR₆R₇, —C(N—OH)NH₂,—C(N—OH)R₈, —CH₂OR₈, —OC(O)NR₆R₇, —SR₉, or —C(O)NR₈SO₂R₉, and R₁, R₂,taken together, may form a ring;

R₃ and R₄ are independently hydrogen, substituted or unsubstituted loweralkyl, —COOH, —COO₈, or —C(O)NR₁₀R₁₁;

R₅ is selected from the group consisting of C₁-C₁₀ alkyl, C₃-C₁₀cycloalkyl, heterocyclyl, and aryl; wherein said C₁-C₁₀ alkyl, C₃-C₁₀cycloalkyl, heterocyclyl, and aryl groups may be substituted with one ormore substituents independently selected from the group consisting of:hydroxyl group, —COOH, oxo, fluorine, thiol, cyano, nitro, —NR₆R₇, C₁-C₆alkylthio, arylthio, C₁-C₆ alkyl, C₁-C₈ fluoro-substituted alkyl, C₁-C₆alkoxy, C₁-C₈ fluoro-substituted alkoxy, —O-aryl, —OC(═O)-alkyl,—OC(═O)-aryl, C₃-C₈ cycloalkyl, C₃-C₈ fluoro-substituted cycloalkyl,C₃-C₈ cycloalkyloxy, C₃-C₈ fluoro-substituted cycloalkyloxy, C₂-C₆alkenyl, C₂-C₆ alkynyl, aryl, —C(═O)—NR₈R₉, C₁-C₆ alkylcarbonyl, C₃-C₈cycloalkylcarbonyl, heterocyclylcarbonyl, —C(═O)-aryl, —C(═O)—O-aryl,C₁-C₆ alkoxycarbonyl, C₁-C₆ fluoro-substituted alkoxycarbonyl, C₃-C₈cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, C₁-C₆ alkylsulfonyl,arylsulfonyl, and heterocyclyl;

wherein when R₅ is aryl, said one or more substitutents further includechlorine, bromine and iodine; and

wherein when R₅ is a heterocycle having an endocyclic nitrogen atom orendocyclic nitrogen atoms, said endocyclic nitrogen atom or endocyclicnitrogen atoms may be substituted with one or more substituentsindependently selected from the group consisting of: hydrogen, C₁-C₆alkyl, C₃-C₈ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,—C(═O)—NR₈R₉, C₁-C₆ alkylcarbonyl, —C(═O)-aryl, —C(═O)—O-aryl, C₁-C₆alkoxycarbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl, and heterocyclyl;

each R₆ and each R₇ are independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted heterocyclyl, and R₆ and R₇, taken together, may form aring;

each R₈ is independently hydrogen, or substituted or unsubstituted loweralkyl;

each R₉ is independently substituted or unsubstituted alkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heterocyclyl, orsubstituted or unsubstituted heteroaryl;

R₁₀ is substituted or unsubstituted lower alkyl, or substituted orunsubstituted aryl;

R₁₁, is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heterocyclyl, orsubstituted or unsubstituted heteroaryl, and R₁₁, taken together withR₁₀, may form a ring; and

R₁₃ is selected from the group consisting of hydrogen, C₁-C₈ alkyl,C₁-C₈ fluoro-substituted alkyl, C₃-C₈ cycloalkyl, C₃-C₈fluoro-substituted cycloalkyl, aryl, halogen-substituted aryl,heteroaryl, and halogen-substituted heteroaryl.

In an embodiment, R₅ is

wherein m is an integer from 1 to 3; n is an integer from 1 to 3; Z ishydrogen, a bond, —C(O)—, —C(O)NR₁₁—, —S(O)₂—, —C(O)NH—S(O)₂—, orCH(OH)—CH₂—Y—, wherein Y is CH₂, O, S, NH, or a bond; and R₁₂ issubstituted or unsubstituted alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocyclyl, or substituted orunsubstituted heteroaryl.

In an embodiment, R₃ and R₄ are hydrogen.

In an embodiment, R₁₃ is hydrogen.

In an embodiment, m+n=4, if m is not equal to n, then the preferredconfiguration is R.

In an embodiment, Z is —S(O)₂— and R₁₂ is 4-chlorophenyl,4-fluorophenyl, 4-cyanophenyl, methyl, or cyclopropyl.

In an embodiment, R₁ is —(CH₂)₀₋₃—C(O)NR₆R₇, —NR₈SO₂R₉, —NR₈C(O)NR₆R₇,—NR₈C(S)NR₆R₇, —OSO₂NR₆R₇, —C(N—OH)NH₂, —C(N—OH)R₁, —CH₂OR₈,—OC(O)NR₆R₇, —SR₉, or —C(O)NR₈SO₂R₉; and R₂ is hydrogen,—(CH₂)₀₋₃—C(O)NR₆R₇, —NR₈SO₂R₉, —NR₈C(O)NR₆R₇, —NR₈C(S)NR₆R₇,—OSO₂NR₆R₇, —C(N—OH)NH₂, —C(N—OH)R₈, —CH₂OR₈, —OC(O)NR₆R₇, —SR₉, or—C(O)NR₈SO₂R₉, and R₁ and R₂, taken together, may form a ring.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula I or a pharmaceutically acceptable saltthereof together with one or more pharmaceutically acceptable carriersor excipients. In an embodiment, the pharmaceutical composition furthercomprises a second chemotherapeutic agent.

The present invention further provides a method of treating a cellproliferative disorder. The method comprises administering to a subjectin need thereof a therapeutically effective amount of a compound offormula I, or a pharmaceutically acceptable salt thereof, or a prodrugor metabolite thereof, in combination with a pharmaceutically acceptablecarrier, wherein said cell proliferative disorder is treated.

In an embodiment, the cells with proliferative disorder contain DNAencoding a RAF, mutant or wild type. In a further embodiment, the cellshave a constitutively enhanced RAF activity. The RAF can be A-RAF,B-RAF, or C-RAF. In an embodiment, B-RAF is a mutant, more specifically,B-RAF^(V600E).

The cell proliferative disorder can be a precancerous condition, or acancer. In an embodiment, the cell proliferative disorder is melanoma,papillary thyroid cancers, colon cancer, or Congenital Nevi.

The present invention further provides a method of modulating B-RAFactivity. The method comprises contacting a cell containing B-RAF genewith an effective amount of a compound of formula II, or apharmaceutically acceptable salt thereof, or a prodrug, metabolite,analog or derivative thereof, wherein said contacting results in saidinhibiting B-RAF activity. In an embodiment, The B-RAF activity is thekinase activity of B-RAF. In an embodiment, the B-RAF is B-RAF^(V600E).

Other features and advantages of the present invention are apparent fromthe additional descriptions provided herein including the differentexamples. The provided examples illustrate different components andmethodology useful in practicing the present invention. The examples donot limit the claimed invention. Based on the present disclosure theskilled artisan can identify and employ other components and methodologyuseful for practicing the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Synthesis of compounds of formula XI.

FIG. 2: Preparation of the guanidinium salts of formula IX.

FIG. 3: Transformation of intermediate XI to compounds of formulas XIIto XV.

FIG. 4: Preparation of phenols of formula XVII and carboxylic acids offormula XIX.

FIG. 5: Effects of compounds on Phospho-MEK in cancer cells. A375 cellswere treated with 0, 12, 37, 111, 333 and 1000 nM of indicated compoundsfor 1 hr. The levels of Phospho-MEK and total-MEK were accessed byimmunoblotting.

FIG. 6: Effects of compounds on Phospho-ERK in cancer cells. A375 cellswere treated with 0, 12, 37, 111, 333 and 1000 nM of indicated compoundsfor 1 hr. The levels of Phospho-ERK and total-ERK were accessed byimmunoblotting.

DETAILED DESCRIPTION OF THE INVENTION 1. The Compounds

The present invention provides imidazooxazole and/or imidazothiazolecompounds and their synthesis.

In an embodiment, the present invention provides compounds of formula Iand their synthesis.

wherein

X is O, S(O)_(p);

p is an integer from 0 to 2;

R₁ is halogen, —CN, —NO₂, —OH, —O—(C₁-C₈ substituted or unsubstitutedalkyl), —O—(C₁-C₈ fluoroalkyl), —(CH₂)₀₋₃—CO₂H, —(CH₂)₀₋₃—C(O)O-alkyl,—(C₁-C₈ substituted or unsubstituted alkyl), —(C₁-C₉ fluoroalkyl),—(C₃-C₈ cycloalkyl), —(C₃-C₈ fluorocycloalkyl), O-aryl(substituted orunsubstituted), —O-heteroaryl (substituted or unsubstituted), —NR₆R₇,—NR₈—C(O)R₉, —NR₈—C(O)-fluoroalkyl, —NR₈—C(O)— aryl(substituted orunsubstituted), —(CH₂)₀₋₃—C(O)NR₆R₇, —NR₉SO₂R₉, —NR₅C(O)NR₆R₇,—NR₈C(S)NR₆R₇, —OSO₂NR₆R₇, —C(N—OH)NH₂, —C(N—OH)R₈, —CH₂OR₈,—OC(O)NR₆R₇, —SR₉, or —C(O)NR₈SO₂R₉;

R₂ is hydrogen, halogen, —CN, —NO₂, —OH, —O—(C₁-C₈ substituted orunsubstituted alkyl), —O—(C₁-C₈ fluoroalkyl), —(CH₂)₀₋₃—CO₂H,—(CH₂)₀₋₃—C(O)O-alkyl, —(C₁-C₈ substituted or unsubstituted alkyl),—(C₁-C₈ fluoroalkyl), —(C₃-C₈ cycloalkyl), —(C₃-C₈ fluorocycloalkyl),O-aryl(substituted or unsubstituted), —O-heteroaryl (substituted orunsubstituted), —NR₆R₇, —NR₈—C(O)R₉, —NR₈—C(O)-fluoroalkyl,—NR₈—C(O)-aryl(substituted or unsubstituted), —(CH₂)₀₋₃—C(O)NR₆R₇,—NR₈SO₂R₉, —NR₈C(O)NR₆R₇, —NR₈C(S)NR₆R₇, —OSO₂NR₆R₇, —C(N—OH)NH₂,—C(N—OH)R₅, —CH₂OR₈, —OC(O)NR₆R₇, —SR₉, or C(O)NR₈SO₂R₉, and R₁, R₂,taken together, may form a ring;

R₃ and R₄ are independently hydrogen, substituted or unsubstituted loweralkyl, —COOH, —COORS, or —C(O)NR₁₀R₁₁;

R₅ is independently selected from the group consisting of C₁-C₁₀ alkyl,C₃-C₁₀ cycloalkyl, heterocyclyl, and aryl; wherein said C₁-C₁₀ alkyl,C₃-C₁₀ cycloalkyl, heterocyclyl, and aryl groups may be substituted withone or more substituents independently selected from the groupconsisting of: hydroxyl group, —COOH, oxo, fluorine, thiol, cyano,nitro, —NR₆R₇, C₁-C₆ alkylthio, arylthio, C₁-C₆ alkyl, C₁-C₈fluoro-substituted alkyl, C₁-C₆ alkoxy, C₁-C₈ fluoro-substituted alkoxy,—O-aryl, —OC(═O)-alkyl, —OC(═O)-aryl, C₃-C₈ cycloalkyl, C₃-C₈fluoro-substituted cycloalkyl, C₃-C₈ cycloalkyloxy, C₃-C₈fluoro-substituted cycloalkyloxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,—C(═O)—NR₈R₉, C₁-C₆ alkylcarbonyl, C₃-C₈ cycloalkylcarbonyl,heterocyclylcarbonyl, —C(═O)-aryl, —C(═O)—O-aryl, C₁-C₆ alkoxycarbonyl,C₁-C₆ fluoro-substituted alkoxycarbonyl, C₃-C₈ cycloalkyloxycarbonyl,heterocyclyloxycarbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl, andheterocyclyl;

wherein when R₅ is aryl, said one or more substitutents further includechlorine, bromine and iodine; and

wherein when R₅ is a heterocycle having an endocyclic nitrogen atom orendocyclic nitrogen atoms, said endocyclic nitrogen atom or endocyclicnitrogen atoms may be substituted with one or more substituentsindependently selected from the group consisting of: hydrogen, C₁-C₆alkyl, C₃-C₈ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,—C(═O)—NR₈R₉, C₁-C₆ alkylcarbonyl, —C(═O)-aryl, —C(═O)—O-aryl, C₁-C₆alkoxycarbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl, and heterocyclyl;

each R₆ and each R₇ are independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted heterocyclyl, and R₆ and R₇, taken together, may form aring;

each R₈ is independently hydrogen, or substituted or unsubstituted loweralkyl;

each R₉ is independently substituted or unsubstituted alkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heterocyclyl, orsubstituted or unsubstituted heteroaryl;

R₁₀ is substituted or unsubstituted lower alkyl, or substituted orunsubstituted aryl;

R₁₁ is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heterocyclyl, orsubstituted or unsubstituted heteroaryl, and R₁₁, taken together withR₁₀, may form a ring; and

R₁₃ is independently selected from the group consisting of hydrogen,C₁-C₈ alkyl, C₁-C₈ fluoro-substituted alkyl, C₃-C₈ cycloalkyl, C₃-C₈fluoro-substituted cycloalkyl, aryl, halogen-substituted aryl,heteroaryl, and halogen-substituted heteroaryl.

The present invention also provides for compounds of formula II andtheir synthesis.

wherein

X is O, S(O)_(p);

m is an integer from 1 to 3;

n is an integer from 1 to 3;

p is an integer from 0 to 2;

Z is hydrogen, a bond, —C(O)—, —C(O)NR₁₁—, —S(O)₂—, —C(O)NH—S(O)₂—, orCH(OH)—CH₂—Y—, wherein Y is CH₂, O, S, NH, or a bond;

R₁ is halogen, —CN, —NO₂, —OH, —O—(C₁-C₈ substituted or unsubstitutedalkyl), —O—(C₁-C₈ fluoroalkyl), —(CH₂)₀₋₃—CO₂H, —(CH₂)₀₋₃—C(O)O-alkyl,—(C₁-C₈ substituted or unsubstituted alkyl), —(C₁-C₈ fluoroalkyl),—(C₃-C₈ cycloalkyl), —(C₃-C₈ fluorocycloalkyl), O-aryl(substituted orunsubstituted), —O-heteroaryl (substituted or unsubstituted), —NR₆R₇,—NR₉—C(O)R₉, —NR₉—C(O)-fluoroalkyl, —NR₈—C(O)— aryl(substituted orunsubstituted), —(CH₂)₀₋₃—C(O)NR₆R₇, —NR₈SO₂R₉, —NR₈C(O)NR₆R₇,—NR₈C(S)NR₆R₇, —OSO₂NR₆R₇, —C(N—OH)NH₂, —C(N—OH)R₉, —CH₂O %,—OC(O)NR₆R₇, —SR₉, or C(O)NR₈SO₂R₉;

R₂ is hydrogen, halogen, —CN, —NO₂, —OH, —O—(C₁-C₈ substituted orunsubstituted alkyl), —O—(C₁-C₉ fluoroalkyl), —(CH₂)₀₋₃—CO₂H,—(CH₂)₀₋₃—C(O)O-alkyl, —(C₁-C₈ substituted or unsubstituted alkyl),—(C₁-C₈ fluoroalkyl), —(C₃-C₈ cycloalkyl), —(C₃-C₈ fluorocycloalkyl),O-aryl(substituted or unsubstituted), —O-heteroaryl (substituted orunsubstituted), —NR₆R₇, —NR₉—C(O)R₉, —NR₈—C(O)-fluoroalkyl,—NR₉—C(O)-aryl (substituted or unsubstituted), —(CH₂)₀₋₃—C(O)NR₆R₇,—NR₈SO₂R₉, —NR₈C(O)NR₆R₇, —NR₈C(S)NR₆R₇, —OSO₂NR₆R₇, —C(N—OH)NH₂,—C(N—OH)R₈, —CH₂Os, —OC(O)N₆R₇, —SR₉, or —C(O)NR₈SO₂R₉, and R₁, R₂,taken together, may form a ring;

R₃ and R₄ are independently hydrogen, substituted or unsubstituted loweralkyl, —COOH, —COOR₈, or —C(O)NR₁₀R₁₁;

each R₆ and each R₇ are independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted heterocyclyl, and R₆ and R₇, taken together, may form aring;

each R₈ is independently hydrogen, or substituted or unsubstituted loweralkyl;

each R₉ is independently substituted or unsubstituted alkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heterocyclyl, orsubstituted or unsubstituted heteroaryl;

R₁₀ is substituted or unsubstituted lower alkyl, or substituted orunsubstituted aryl;

R₁₁ is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heterocyclyl, orsubstituted or unsubstituted heteroaryl, and R₁₁, taken together withR₁₀, may form a ring;

R₁₂ is substituted or unsubstituted alkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heterocyclyl, or substituted orunsubstituted heteroaryl; and

R₁₃ is independently selected from the group consisting of hydrogen,C₁-C₈ alkyl, C₁-C₈ fluoro-substituted alkyl, C₃-C₈ cycloalkyl, C₃-C₈fluoro-substituted cycloalkyl, aryl, halogen-substituted aryl,heteroaryl, and halogen-substituted heteroaryl.

In an embodiment, R₁ is —(CH₂)₀₋₃—C(O)NR₆R₇, —NR₉SO₂R₅, —NR₈C(O)NR₆R₇,—NR₉C(S)NR₆R₇, —OSO₂NR₆R₇, —C(N—OH)NH₂, —C(N—OH)R₅, —CH₂OR₉,—OC(O)NR₆R₇, —SR₉, or C(O)NR₈SO₂R₉; and R₂ is hydrogen,—(CH₂)₀₋₃—C(O)NR₆R₇, —NR₈SO₂R₉, —NR₈C(O)NR₆R₇, —NR₈C(S)NR₆R₇,—OSO₂NR₆R₇, —C(N—OH)NH₂, —C(N—OH)R₈, —CH₂OR₈, —OC(O)NR₆R₇, —SR₉, or—C(O)NR₈SO₂R₉, and R₁, R₂, taken together, may form a ring.

The term “alkyl” refers to radicals containing carbon and hydrogen,without unsaturation. Alkyl radicals can be straight or branched.Exemplary alkyl radicals include, without limitation, methyl, ethyl,propyl, isopropyl, hexyl, t-butyl, sec-butyl and the like. Alkyl groupsmay be denoted by a range, thus, for example, a (C₁-C₆) alkyl group isan alkyl group having from one to six carbon atoms in the straight orbranched alkyl backbone. Substituted and unsubstituted alkyl groups mayindependently be (C₁-C₅) alkyl, (C₁-C₆) alkyl, (C₁-C₁₀) alkyl, (C₃-C₁₀)alkyl, or (C₅-C₁₀) alkyl. Unless expressly stated, the term “alkyl” doesnot include “cycloalkyl.” The term “lower alkyl” refers to unbranched orbranched (C₁-C₆) alkyl.

A “cycloalkyl” group refers to a cyclic alkyl group having the indicatednumber of carbon atoms in the “ring portion,” where the “ring portion”may consist of one or more ring structures either as fused, spiro, orbridged ring structures. For example, a C₃ to C₆ cycloalkyl group (e.g.,(C₃-C₆) cycloalkyl) is a ring structure having between 3 and 6 carbonatoms in the ring. When no range is given, then cycloalkyl has betweenthree and nine carbon atoms ((C₃-C₉) cycloalkyl) in the ring portion.Exemplary cycloalkyl groups include, but are not limited to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.Preferred cycloalkyl groups have three, four, five, six, seven, eight,nine, or from three to nine carbon atoms in the ring structure.

The term substituted alkyl and substituted cycloalkyl, refer to alkyland cycloalkyl groups, as defined above, substituted with one or moresubstituents independently selected from the group consisting offluorine, aryl, heteroaryl, —O—(C₁-C₆) alkyl, and —NR5R6, where R5 andR6 are independently selected from the group consisting of hydrogen and—(C₁-C₆) alkyl.

The term “aryl” refers to an aromatic carbocyclic group, having one,two, or three aromatic rings. Exemplary aryl groups include, withoutlimitation, phenyl, naphthyl, and the like. Aryl groups include one,two, or three aromatic rings structures fused with one or moreadditional nonaromatic carbocyclic or hetercyclic rings having from 4-9members. Examples of fused aryl groups include benzocyclobutanyl,indanyl, tetrahydronapthylenyl, 1,2,3,4-tetrahydrophenanthrenyl,tetrahydroanthracenyl, 1,4-dihydro-1,4-methanonaphthalenyl,benzodioxolyl.

The term “heteroaryl” refers to a heteroaromatic (heteroaryl) grouphaving one, two, or three aromatic rings containing from 1-4 heteroatoms(such as nitrogen, sulfur, or oxygen) in the aromatic ring. Heteroarylgroups include one, two, or three aromatic rings structures containingfrom 1-4 heteroatoms fused with one or more additional nonaromatic ringshaving from 4-9 members. Heteroaryl groups containing a single type ofhetroatom in the aromatic ring are denoted by the type of hetero atomthey contain, thus, nitrogen-containing heteroaryl, oxygen-containingheteroaryl and sulfur-containing heteroaryl denote heteroaromatic groupscontaining one or more nitrogen, oxygen or sulfur atoms respectively.Exemplary heteroaryl groups include, without limitation, pyridyl,pyrimidinyl, triazolyl, quinolyl, quinazolinyl, thiazolyl,benzo[b]thiophenyl, furanyl, imidazolyl, indolyl, and the like.

The terms “heterocyclyl” or “heterocycle” refers to either saturated orunsaturated, stable non-aromatic ring structures that may be fused,spiro or bridged to form additional rings. Each heterocycle consists ofone or more carbon atoms and from one to four heteroatoms selected fromthe group consisting of nitrogen, oxygen and sulfur. “Heterocyclyl” or“heterocycle” include stable non-aromatic 3-7 membered monocyclicheterocyclic ring structures and 8-11 membered bicyclic heterocyclicring structures. A heterocyclyl radical may be attached at anyendocyclic carbon or nitrogen atom that results in the creation of astable structure. Preferred heterocycles include 3-7 membered monocyclicheterocycles (more preferably 5-7-membered monocyclic heterocycles) and8-10 membered bicyclic heterocycles. Examples of such groups includepiperidinyl, piperazinyl, pyranyl, pyrrolidinyl, morpholmyl,thiomorpholinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl,isoxozolyl, tetrahydropyranyl, tetrahydrofuranyl, dioxolyl, dioxinyl,oxathiofyl, dithiolyl, sulfolanyl, dioxanyl, dioxolanyl,tetahydrofurodihydrofuranyl, tetrahydropyranodihydro-furanyl,dihydropyranyl, tetrahydrofurofuranyl, tetrahydropyranofuran,quinuclidinyl (1-azabicyclo[2.2.2]octanyl) and tropanyl(8-methyl-8-azabicyclo[3.2.1]octanyl).

All stereoisomers of the compounds of the instant invention arecontemplated, either in a mixture or in pure or substantially pure form,including crystalline forms of racemic mixtures and crystalline forms ofindividual isomers. The definition of the compounds according to theinvention embraces all possible stereoisomers (e.g., the R and Sconfigurations for each asymmetric center) and their mixtures. It veryparticularly embraces the racemic forms and the isolated optical isomershaving a specified activity. The racemic forms can be resolved byphysical methods, such as, for example, fractional crystallization,separation or crystallization of diastereomeric derivatives, separationby chiral column chromatography or supercritical fluid chromatography.The individual optical isomers can be obtained from the racemates byconventional methods, such as, for example, salt formation with anoptically active acid followed by crystallization. Furthermore, allgeometric isomers, such as E- and Z-configurations at a double bond, arewithin the scope of the invention unless otherwise stated. Certaincompounds of this invention may exist in tautomeric forms. All suchtautomeric forms of the compounds are considered to be within the scopeof this invention unless otherwise stated. The present invention alsoincludes one or more regioisomeric mixtures of an analog or derivative.

As used herein, the term “salt” is a pharmaceutically acceptable saltand can include acid addition salts including hydrochlorides,hydrobromides, phosphates, sulphates, hydrogen sulphates,alkylsulphonates, arylsulphonates, acetates, benzoates, citrates,maleates, fumarates, succinates, lactates, and tartrates; alkali metalcations such as Na⁺, K⁺, Li⁺, alkali earth metal salts such as M²⁺ orCa²⁺, or organic amine salts.

As used herein, the term “metabolite” means a product of metabolism of acompound of the present invention, or a pharmaceutically acceptablesalt, analog or derivative thereof, that exhibits a similar activity invivo to said compound of the present invention.

As used herein, the term “prodrug” means a compound of the presentinvention covalently linked to one or more pro-moieties, such as anamino acid moiety or other water solubilizing moiety. A compound of thepresent invention may be released from the pro-moiety via hydrolytic,oxidative, and/or enzymatic release mechanisms. In an embodiment, aprodrug composition of the present invention exhibits the added benefitof increased aqueous solubility, improved stability, and improvedpharmacokinetic profiles. The pro-moiety may be selected to obtaindesired prodrug characteristics. For example, an amino acid moiety orother water solubilizing moiety such as phosphate within R₄, may beselected based on solubility, stability, bioavailability, and/or in vivodelivery or uptake. In an embodiment of the present invention, thecompound is a compound of formula I or formula II wherein R₃ and R₄ arehydrogen.

In another embodiment of the present invention, the compound is acompound of formula I or formula II wherein R₁ is 3-OH and R₂ ishydrogen.

In another embodiment of the present invention, the compound is acompound of formula I or formula II wherein R₁₃ is hydrogen.

In another embodiment of the present invention, the compound is acompound of formula II wherein m+n=4, m is not equal to n, and theconfiguration is R. As used herein, the configuration of a molecule isthe permanent geometry that results from the spatial arrangement of itsatoms. The configuration can be either R or S and is defined accordingto the UIPAC rules. When more than one stereogenic atoms are present ina molecule, each one will be defined as of configuration R or S.

In another embodiment of the present invention, the compound is acompound of formula I or formula II wherein Z is —S(O)₂— and R₁₂ is4-chlorophenyl, 4-fluorophenyl or 4-cyanophenyl.

In an embodiment of the present invention, the compound is one ofcompounds #1-316 listed in table 2. In a further embodiment of thepresent invention, thecompound is one of compounds #1-289 listed intable 2. In an embodiment of the present invention, the compound is oneof compounds #290-316 listed in table 2. In an embodiment of the presentinvention, the compound is one of compounds #317-401 listed in table 2.

In an embodiment of the present invention, the compound is3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenylcarbamate,3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenylsulfamate,3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenylsulfamate,3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenylcarbamate,(1E)-1-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanoneoxime,2-chloro-5-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenol,4-([(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl)amino)piperidin-1-yl]sulfonyl}benzonitrile,4-{[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfonyl}benzoicacid,3-{[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfonyl}phenol,2-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzene-1,4-diol,3-[5-(2-{[(3R)-1-(methylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,3-{5-[2-({1-[(4-fluorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,3-{5-[2-({1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,N-ethyl-4-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxamide,3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,4-{[4-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfonyl}benzonitrile,4-{[4-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfonyl}benzamide,4-{[(3R)-3-({4-[6-(3-hydroxyphenyl)idazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfonyl}benzonitrile,3-{5-[2-({1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenol,3-{5-[2-({1-[(4-fluorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenol,5-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]triazol-6-yl}-2-fluorophenol,3-{5-[2-({(3R)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,3-[5-(2-{[(3R)-1-(3-thienylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,3-[5-(2-{[(3R)-1-(2-thienylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,3-[5-(2-{[(3R)-1-(phenylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,3-(5-[2-({(3R)-1-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl)phenol,3-[5-(2-{[(3R)-1-(4H-1,2,4-triazol-3-ylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,3-[5-(2-{[(3R)-1-(2-thienylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol,3-[5-(2-{[(3R)-1-(phenylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol,3-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,3-[5-(2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,3-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol,3-[5-(2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol,5-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]-2-fluorophenol,or3-[5-(2-{[(3R)-1-(cyclopropylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol.

In a further embodiment of the present invention, the compound is3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenylcarbamate,3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenylsulfamate,3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenylsulfamate,3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenylcarbamate, or(1E)-1-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanoneoxime.

In an alternative embodiment of the present invention, the compound is3-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,3-[5-(2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,3-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol,3-[5-(2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol,5-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]-2-fluorophenol,or3-[5-(2-{[(3R)-1-(cyclopropylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol.

2. Methods and Intermediates for Preparing Compounds of the Invention

Standard synthetic methods and procedures for the preparation of organicmolecules and functional group transformations and manipulationsincluding the use of protective groups can be obtained from the relevantscientific literature or from standard reference textbooks in the field.Although not limited to any one or several sources, recognized referencetextbooks of organic synthesis include: Smith, M. B.; March, J. March'sAdvanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5^(th)ed.; John Wiley & Sons: New York, 2001; and Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 3R^(d); John Wiley & Sons:New York, 1999. The following descriptions of synthetic methods aredesigned to illustrate, but not limit, general procedures for thepreparation of compounds of the invention.

Compounds of the invention can be prepared in a variety of ways, some ofwhich are known in the art. In general, the compounds of the presentinvention can be prepared from commercially available startingmaterials, compounds known in the literature, or from readily-preparedintermediates, by employing standard synthetic methods and proceduresknown to those skilled in the art, or which will be apparent to theskilled artisan in light of the teachings herein. Standard syntheticmethods and procedures for the preparation of organic molecules andfunctional group transformations and manipulations can be obtained fromthe relevant scientific literature or from standard textbooks in thefield. The description of the synthesis of some compounds of the presentinvention can also be found in PCT patent publications WO 2004/110990,and WO 2006/010082, and WO 2006/044869.

A method for preparing imidazooxazole and imidazothiazole compounds ofthe invention is described in the Examples below and illustrated inFIG. 1. In FIG. 1, step a, a suitably substituted α-haloketone III isreacted with an optionally substituted 2-aminooxazole IV. This reactionis typically conducted in inert organic solvent such as acetonitrile orsimilar at room temperature. The product (not shown) is typicallyisolated from the reaction mixture as a solid hydrogen bromide salt byfiltration. The cyclization of the hydrogen bromide intermediate toyield the imidazooxazole compound V is conveniently performed by theaddition of a dehydrating reagent, such as titanium tetrachloride. Thisreaction, following appropriate pH modification of the resultingreaction mixture, provides V. In the case of the imidazothiazolecompounds, step b, a suitably substituted α-haloketone III is reactedwith an optionally substituted 2-aminothiazole IV. This reaction istypically conducted in a solvent such as ethanol at reflux to yieldcompound V directly. The compounds V are purified by chromatography orby trituration in an inert solvent such as diethylether. Acetylation ofcompounds V (step c) is typically done in acetic anhydride, usingconcentrated sulfuric acid in catalytic amount, providing compounds VI.The compounds VI are typically purified by chromatography. The ketonesVI are converted to the enaminones VIII by reaction with DMF-DME at hightemperature or by mean of microwave activation (step d). Typically, thesolid enaminones VIII can be purified by chromatography or bytrituration in an inert solvent such as diethylether. The enaminonesVIII are cyclized to intermediate X (step f) by reaction with theguanidinium salt IX in a suitable solvent such as ethanol, at elevatedtemperature, typically reflux and using a base such as sodium ethoxide.The compounds X can be purified by chromatography or by trituration inan inert solvent such as diethylether. The BOC protective group issuitably removed using HCl solution, typically 4N in dioxane, to yieldthe compounds XI (step g). Compounds XI are typically hydrogen chloridesalts and can be used without purification.

The preparation of the guanidinium hydrochloride is illustrated in FIG.2. Typically, an amine such as tert-butyl4-aminopiperidine-1-carboxylate is reacted with pyrazole carboxamidinehydrochloride in an appropriate solvent such as DMF at elevatedtemperature, in the presence of a tertiary amine such as Hunig's base.The product IX is purified by repetitive trituration in an inert solventsuch as diethylether.

The functionalization of the amine XI is illustrated in FIG. 3.Typically, compounds XI are reacted with an appropriately substitutedisocyanate (step h) in an inert solvent such as tetrahydrofuran, in thepresence of a tertiary amine such as triethylamine, at room temperatureor at an elevated temperature. The compounds XII are purified bychromatography or by trituration in an inert solvent such asdiethylether. Sulfonamides XIII are prepared by reacting compounds XIwith an appropriately substituted sulfonyl chloride in an inert solventsuch as methylene chloride, in the presence of a tertiary amine such asHunig's base, at room temperature or at elevated temperature (step i).Compounds XIII are purified by chromatography or by trituration in aninert solvent such as diethylether. Compounds XIV can be prepared usingany coupling reagent and a carboxylic acid or by using an acyl halide.For example, compounds XI are reacted with a suitably substituted acidchloride in the presence of a tertiary amine such as triethylamine, inan inert solvent such as methylene chloride, at room temperature orelevated temperature (step j). Compounds XIV are purified bychromatography or by trituration in an inert solvent such asdiethylether. In another example, compounds XI are reacted with asuitably substituted carboxylic acid using HBTU as a coupling reagent inthe presence of DMAP and triethylamine, in an inert solvent such as DMF,at room temperature or elevated temperature (step k). Compounds XIV arepurified by chromatography or by trituration in an inert solvent such asdiethylether. Compounds XV are prepared by reacting compounds XI with anappropriately substituted aldehyde in the presence of a reducing agentsuch as Me₄NBH(OAc)₃ in an inert solvent such as DCE, at roomtemperature or elevated temperature (step 1). Compounds XV are purifiedby chromatography or by trituration in an inert solvent such asdiethylether.

The preparation of compounds XVIII and XIX is illustrated in FIG. 4.Compounds XVI are reacted with excess boron tribromide in an inertsolvent such as methylene chloride, at low temperature, typically −78°C. After all starting material has been consumed, the reaction iscarefully quench with an alcohol, typically methanol, at low temperature(from −78° C. to 0° C.). The product XVII is purified by chromatographyor by trituration in an inert solvent such as diethylether. CompoundsXIX are prepared by reacting compounds XVIII with an hydroxide,typically lithium hydroxide, in an appropriate solvent such astetrahydrofuran, at room temperature or elevated temperature. CompoundsXIX are purified by chromatography or by trituration in an inert solventsuch as diethylether.

3. Methods of Treatment

The compounds of the present invention can be used for the treatment andor prevention of cell proliferative disorder such as cancer. Thecompounds of the present invention are capable of inhibiting the RAFprotein kinases. Thus, the compounds can be used for the treatment ofcell proliferative disorder characterized by aberrant RAS-RAF signaling.In an embodiment, the cells of cell proliferative disorder such ascancer harbor a mutated B-RAF. In a further embodiment, the mutatedB-RAF is a B-RAF with the V600E mutation (B-RAF^(V600E)). The cellproliferative disorder can be melanomas, papillary thyroid cancers,colon cancers.

The present invention also provides a method of treating any otherconditions characterized by a B-RAF^(V600E), e.g., Congenital Nevi(commonly known as moles or freckles) possessing the B-RAF^(V600E), withthe imidazooxazole and/or imidazothiazole compounds. In a furtherembodiment, the present invention may be used prophylactically (e.g.,topically applied to the skin) to prevent such nevi to develop intomalignant melanomas.

As used herein, a “subject” can be any mammal, e.g. a human, a primate,mouse, rat, dog, cat, cow, horse, pig, sheep, goat, camel. In apreferred aspect, the subject is a human.

As used herein, a “subject in need thereof” is a subject having a cellproliferative disorder, or a subject having an increased risk ofdeveloping a cell proliferative disorder relative to the population atlarge. In one aspect, a subject in need thereof has a precancerouscondition. In a preferred aspect, a subject in need thereof has cancer.

As used herein, the term “cell proliferative disorder” refers toconditions in which unregulated or abnormal growth, or both, of cellscan lead to the development of an unwanted condition or disease, whichmay or may not be cancerous. In one aspect, a cell proliferativedisorder includes a non-cancerous condition, e.g. rheumatoid arthritis;inflammation; autoimmune disease; lymphoproliferative conditions;acromegaly; rheumatoid spondylitis; osteoarthritis; gout, otherarthritic conditions; sepsis; septic shock; endotoxic shock;gram-negative sepsis; toxic shock syndrome; asthma; adult respiratorydistress syndrome; chronic obstructive pulmonary disease; chronicpulmonary inflammation; inflammatory bowel disease; Crohn's disease;psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepaticfibrosis; acute and chronic renal disease; irritable bowel syndrome;pyresis; restenosis; cerebral malaria; stroke and ischemic injury;neural trauma; Alzheimer's disease; Huntington's disease; Parkinson'sdisease; acute and chronic pain; allergic rhinitis; allergicconjunctivitis; chronic heart failure; acute coronary syndrome;cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter'ssyndrome; acute synovitis; muscle degeneration, bursitis; tendonitis;tenosynovitis; herniated, ruptures, or prolapsed intervertebral disksyndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonarysarcosis; bone resorption diseases, such as osteoporosis;graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia;AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I orII, influenza virus and cytomegalovirus; and diabetes mellitus. Inanother aspect, a cell proliferative disorder includes a precancer or aprecancerous condition. In another aspect, a cell proliferative disorderincludes cancer. Various cancers to be treated include but are notlimited to breast cancer, lung cancer, colorectal cancer, pancreaticcancer, ovarian cancer, prostate cancer, renal carcinoma, hepatoma,brain cancer, melanoma, multiple myeloma, chronic myelogenous leukemia,hematologic tumor, and lymphoid tumor, including metastatic lesions inother tissues or organs distant from the primary tumor site. Cancers tobe treated include but are not limited to sarcoma, carcinoma, andadenocarcinoma. In one aspect, a “precancer cell” or “precancerous cell”is a cell manifesting a cell proliferative disorder that is a precanceror a precancerous condition. In another aspect, a “cancer cell” or“cancerous cell” is a cell manifesting a cell proliferative disorderthat is a cancer. Any reproducible means of measurement may be used toidentify cancer cells or precancerous cells. In a preferred aspect,cancer cells or precancerous cells are identified by histological typingor grading of a tissue sample (e.g., a biopsy sample). In anotheraspect, cancer cells or precancerous cells are identified through theuse of appropriate molecular markers.

A “cell proliferative disorder of the colon” is a cell proliferativedisorder involving cells of the colon. In a preferred aspect, the cellproliferative disorder of the colon is colon cancer. In a preferredaspect compositions of the present invention may be used to treat coloncancer or cell proliferative disorders of the colon. In one aspect,colon cancer includes all forms of cancer of the colon. In anotheraspect, colon cancer includes sporadic and hereditary colon cancers. Inanother aspect, colon cancer includes malignant colon neoplasms,carcinoma in situ, typical carcinoid tumors, and atypical carcinoidtumors. In another aspect, colon cancer includes adenocarcinoma,squamous cell carcinoma, and adenosquamous cell carcinoma. In anotheraspect, colon cancer is associated with a hereditary syndrome selectedfrom the group consisting of hereditary nonpolyposis colorectal cancer,familial adenomatous polyposis, Gardner's syndrome, Peutz-Jegherssyndrome, Turcot's syndrome and juvenile polyposis. In another aspect,colon cancer is caused by a hereditary syndrome selected from the groupconsisting of hereditary nonpolyposis colorectal cancer, familialadenomatous polyposis, Gardner's syndrome, Peutz-Jeghers syndrome,Turcot's syndrome and juvenile polyposis.

In one aspect, cell proliferative disorders of the colon include allforms of cell proliferative disorders affecting colon cells. In oneaspect, cell proliferative disorders of the colon include colon cancer,precancerous conditions of the colon, adenomatous polyps of the colonand metachronous lesions of the colon. In one aspect, a cellproliferative disorder of the colon includes adenoma. In one aspect,cell proliferative disorders of the colon are characterized byhyperplasia, metaplasia, and dysplasia of the colon. In another aspect,prior colon diseases that may predispose individuals to development ofcell proliferative disorders of the colon include prior colon cancer. Inanother aspect, current disease that may predispose individuals todevelopment of cell proliferative disorders of the colon include Crohn'sdisease and ulcerative colitis. In one aspect, a cell proliferativedisorder of the colon is associated with a mutation in a gene selectedfrom the group consisting of p53, ras, FAP and DCC. In another aspect,an individual has an elevated risk of developing a cell proliferativedisorder of the colon due to the presence of a mutation in a geneselected from the group consisting of p53, ras, FAP and DCC.

A “cell proliferative disorder of the skin” is a cell proliferativedisorder involving cells of the skin. In one aspect, cell proliferativedisorders of the skin include all forms of cell proliferative disordersaffecting skin cells. In one aspect, cell proliferative disorders of theskin include a precancer or precancerous condition of the skin, benigngrowths or lesions of the skin, melanoma, malignant melanoma and othermalignant growths or lesions of the skin, and metastatic lesions intissue and organs in the body other than the skin. In another aspect,cell proliferative disorders of the skin include hyperplasia,metaplasia, and dysplasia of the skin.

In one aspect, a cancer that is to be treated has been staged accordingto the American Joint Committee on Cancer (AJCC) TNM classificationsystem, where the tumor (T) has been assigned a stage of TX, T1, T1mic,T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c, or T4d; and where the regionallymph nodes (N) have been assigned a stage of NX, N0, N1, N2, N2a, N2b,N3, N3a, N3b, or N3c; and where distant metastasis (M) has been assigneda stage of MX, M0, or M1. In another aspect, a cancer that is to betreated has been staged according to an American Joint Committee onCancer (AJCC) classification as Stage I, Stage IIA, Stage IIB, StageIIIA, Stage IIIB, Stage IIIC, or Stage IV. In another aspect, a cancerthat is to be treated has been assigned a grade according to an AJCCclassification as Grade GX (e.g., grade cannot be assessed), Grade 1,Grade 2, Grade 3 or Grade 4. In another aspect, a cancer that is to betreated has been staged according to an AJCC pathologic classification(pN) of pNX, pN0, PN0 (I−), PN0 (I+), PN0 (mol−), PN0 (mol+), PN1,PN1(mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.

In one aspect, a cancer that is to be treated includes a tumor that hasbeen determined to be less than or equal to about 2 centimeters indiameter. In another aspect, a cancer that is to be treated includes atumor that has been determined to be from about 2 to about 5 centimetersin diameter. In another aspect, a cancer that is to be treated includesa tumor that has been determined to be greater than or equal to about 3centimeters in diameter. In another aspect, a cancer that is to betreated includes a tumor that has been determined to be greater than 5centimeters in diameter. In another aspect, a cancer that is to betreated is classified by microscopic appearance as well differentiated,moderately differentiated, poorly differentiated, or undifferentiated.In another aspect, a cancer that is to be treated is classified bymicroscopic appearance with respect to mitosis count (e.g., amount ofcell division) or nuclear pleiomorphism (e.g., change in cells). Inanother aspect, a cancer that is to be treated is classified bymicroscopic appearance as being associated with areas of necrosis (e.g.,areas of dying or degenerating cells). In one aspect, a cancer that isto be treated is classified as having an abnormal karyotype, having anabnormal number of chromosomes, or having one or more chromosomes thatare abnormal in appearance. In one aspect, a cancer that is to betreated is classified as being aneuploid, triploid, tetraploid, or ashaving an altered ploidy. In one aspect, a cancer that is to be treatedis classified as having a chromosomal translocation, or a deletion orduplication of an entire chromosome, or a region of deletion,duplication or amplification of a portion of a chromosome.

In one aspect, a cancer that is to be treated is evaluated by DNAcytometry, flow cytometry, or image cytometry. In one aspect, a cancerthat is to be treated has been typed as having 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, or 90% of cells in the synthesis stage of cell division(e.g., in S phase of cell division). In one aspect, a cancer that is tobe treated has been typed as having a low S-phase fraction or a highS-phase fraction.

As used herein, a “normal cell” is a cell that cannot be classified aspart of a “cell proliferative disorder.” In one aspect a normal celllacks unregulated or abnormal growth, or both, that can lead to thedevelopment of an unwanted condition or disease. Preferably, a normalcell possesses normally functioning cell cycle checkpoint controlmechanisms.

As used herein, “contacting a cell” refers to a condition in which acompound or other composition of matter is in direct contact with acell, or is close enough to induce a desired biological effect in acell.

As used herein, “candidate compound” refers to a compound of the presentinvention that has been or will be tested in one or more in vitro or invivo biological assays, in order to determine if that compound is likelyto elicit a desired biological or medical response in a cell, tissue,system, animal or human that is being sought by a researcher orclinician. In one aspect, a candidate compound is a compound of formulaII; in another aspect, a candidate compound is a compound of formula I.In a preferred aspect, the biological or medical response is treatmentof cancer. In another aspect the biological or medical response istreatment or prevention of a cell proliferative disorder. In one aspect,in vitro or in vivo biological assays include, but are not limited to,enzymatic activity assays, electrophoretic mobility shift assays,reporter gene assays, in vitro cell viability assays.

As used herein, “monotherapy” refers to administration of a singleactive or therapeutic compound to a subject in need thereof. Preferably,monotherapy will involve administration of a therapeutically effectiveamount of an active compound. For example, cancer monotherapy with3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenolcomprises administration of a therapeutically effective amount of3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,or a pharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof, to a subject in need of treatment of cancer.Monotherapy may be contrasted with combination therapy, in which acombination of multiple active compounds is administered, preferablywith each component of the combination present in a therapeuticallyeffective amount. In one aspect, montherapy with a compound of thepresent invention is more effective than combination therapy in inducinga desired biological effect.

As used herein, “treating” describes the management and care of apatient for the purpose of combating a disease, condition, or disorderand includes the administration of a compound of the present inventionto prevent the onset of the symptoms or complications, alleviating thesymptoms or complications, or eliminating the disease, condition ordisorder.

In one aspect, treating cancer results in a reduction in size of atumor. A reduction in size of a tumor may also be referred to as “tumorregression.” Preferably, after treatment, tumor size is reduced by 5% orgreater relative to its size prior to treatment; more preferably, tumorsize is reduced by 10% or greater; more preferably, reduced by 20% orgreater; more preferably, reduced by 30% or greater; more preferably,reduced by 40% or greater; even more preferably, reduced by 50% orgreater; and most preferably, reduced by greater than 75% or greater.Size of a tumor may be measured by any reproducible means ofmeasurement. In a preferred aspect, size of a tumor may be measured as adiameter of the tumor.

In another aspect, treating cancer results in a reduction in tumorvolume. Preferably, after treatment, tumor volume is reduced by 5% orgreater relative to its size prior to treatment; more preferably, tumorvolume is reduced by 10% or greater; more preferably, reduced by 20% orgreater; more preferably, reduced by 30% or greater; more preferably,reduced by 40% or greater; even more preferably, reduced by 50% orgreater; and most preferably, reduced by greater than 75% or greater.Tumor volume may be measured by any reproducible means of measurement.

In another aspect treating cancer results in a decrease in number oftumors. Preferably, after treatment, tumor number is reduced by 5% orgreater relative to number prior to treatment; more preferably, tumornumber is reduced by 10% or greater; more preferably, reduced by 20% orgreater, more preferably, reduced by 30% or greater; more preferably,reduced by 40% or greater, even more preferably, reduced by 50% orgreater; and most preferably, reduced by greater than 75%. Number ofrumors may be measured by any reproducible means of measurement. In apreferred aspect, number of tumors may be measured by counting tumorsvisible to the naked eye or at a specified magnification. In a preferredaspect, the specified magnification is 2×, 3×, 4×, 5×, 10×, or 50×.

In another aspect, treating cancer results in a decrease in number ofmetastatic lesions in other tissues or organs distant from the primarytumor site. Preferably, after treatment, the number of metastaticlesions is reduced by 5% or greater relative to number prior totreatment; more preferably, the number of metastatic lesions is reducedby 10% or greater; more preferably, reduced by 20% or greater; morepreferably, reduced by 30% or greater; more preferably, reduced by 40%or greater; even more preferably, reduced by 50% or greater; and mostpreferably, reduced by greater than 75%. The number of metastaticlesions may be measured by any reproducible means of measurement. In apreferred aspect, the number of metastatic lesions may be measured bycounting metastatic lesions visible to the naked eye or at a specifiedmagnification. In a preferred aspect, the specified magnification is 2×,3×, 4×, 5×, 10×, or 50×.

In another aspect, treating cancer results in an increase in averagesurvival time of a population of treated subjects in comparison to apopulation receiving carrier alone. Preferably, the average survivaltime is increased by more than 30 days; more preferably, by more than 60days; more preferably, by more than 90 days; and most preferably, bymore than 120 days. An increase in average survival time of a populationmay be measured by any reproducible means. In a preferred aspect anincrease in average survival time of a population may be measured, forexample, by calculating for a population the average length of survivalfollowing initiation of treatment with an active compound. In anotherpreferred aspect, an increase in average survival time of a populationmay also be measured, for example, by calculating for a population theaverage length of survival following completion of a first round oftreatment with an active compound.

In another aspect, treating cancer results in an increase in averagesurvival time of a population of treated subjects in comparison to apopulation of untreated subjects. Preferably, the average survival timeis increased by more than 30 days; more preferably, by more than 60days; more preferably, by more than 90 days; and most preferably, bymore than 120 days. An increase in average survival time of a populationmay be measured by any reproducible means. In a preferred aspect, anincrease in average survival time of a population may be measured, forexample, by calculating for a population the average length of survivalfollowing initiation of treatment with an active compound. In anotherpreferred aspect, an increase in average survival time of a populationmay also be measured, for example, by calculating for a population theaverage length of survival following completion of a first round oftreatment with an active compound.

In another aspect, treating cancer results in increase in averagesurvival time of a population of treated subjects in comparison to apopulation receiving monotherapy with a drug that is not a compound ofthe present invention, or a pharmaceutically acceptable salt, prodrug,metabolite, analog or derivative thereof. Preferably, the averagesurvival time is increased by more than 30 days; more preferably, bymore than 60 days; more preferably, by more than 90 days; and mostpreferably, by more than 120 days. An increase in average survival timeof a population may be measured by any reproducible means. In apreferred aspect, an increase in average survival time of a populationmay be measured, for example, by calculating for a population theaverage length of survival following initiation of treatment with anactive compound. In another preferred aspect, an increase in averagesurvival time of a population may also be measured, for example, bycalculating for a population the average length of survival followingcompletion of a first round of treatment with an active compound.

In another aspect, treating cancer results in a decrease in themortality rate of a population of treated subjects in comparison to apopulation receiving carrier alone. In another aspect, treating cancerresults in a decrease in the mortality rate of a population of treatedsubjects in comparison to an untreated population. In a further aspect,treating cancer results a decrease in the mortality rate of a populationof treated subjects in comparison to a population receiving monotherapywith a drug that is not a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof. Preferably, the mortality rate is decreased by morethan 2%; more preferably, by more than 5%; more preferably, by more than10%; and most preferably, by more than 25%. In a preferred aspect, adecrease in the mortality rate of a population of treated subjects maybe measured by any reproducible means. In another preferred aspect, adecrease in the mortality rate of a population may be measured, forexample, by calculating for a population the average number ofdisease-related deaths per unit time following initiation of treatmentwith an active compound. In another preferred aspect, a decrease in themortality rate of a population may also be measured; for example, bycalculating for a population the average number of disease-relateddeaths per unit time following completion of a first round of treatmentwith an active compound.

In another aspect, treating cancer results in a decrease in tumor growthrate. Preferably, after treatment, tumor growth rate is reduced by atleast 5% relative to number prior to treatment; more preferably, tumorgrowth rate is reduced by at least 10%; more preferably, reduced by atleast 20%; more preferably, reduced by at least 30%; more preferably,reduced by at least 40%; more preferably, reduced by at least 50%; evenmore preferably, reduced by at least 50%; and most preferably, reducedby at least 75%. Tumor growth rate may be measured by any reproduciblemeans of measurement. In a preferred aspect, tumor growth rate ismeasured according to a change in tumor diameter per unit time.

In another aspect, treating cancer results in a decrease in tumorregrowth. Preferably, after treatment, tumor regrowth is less than 5%;more preferably, tumor regrowth is less than 10%; more preferably, lessthan 20%; more preferably, less than 30%; more preferably, less than40%; more preferably, less than 50%; even more preferably, less than50%; and most preferably, less than 75%. Tumor regrowth may be measuredby any reproducible means of measurement. In a preferred aspect, tumorregrowth is measured, for example, by measuring an increase in thediameter of a tumor after a prior tumor shrinkage that followedtreatment. In another preferred aspect, a decrease in tumor regrowth isindicated by failure of tumors to reoccur after treatment has stopped.

In another aspect, treating or preventing a cell proliferative disorderresults in a reduction in the rate of cellular proliferation.Preferably, after treatment, the rate of cellular proliferation isreduced by at least 5%; more preferably, by at least 10%; morepreferably, by at least 20%; more preferably, by at least 30%; morepreferably, by at least 40%; more preferably, by at least 50%; even morepreferably, by it least 50%; and most preferably, by at least 75%. Therate of cellular proliferation may be measured by any reproducible meansof measurement. In a preferred aspect, the rate of cellularproliferation is measured, for example, by measuring the number ofdividing cells in a tissue sample per unit time.

In another aspect, treating or preventing a cell proliferative disorderresults in a reduction in the proportion of proliferating cells.Preferably, after treatment, the proportion of proliferating cells isreduced by at least 5%; more preferably, by at least 10%; morepreferably, by at least 20%; more preferably, by at least 30%; morepreferably, by at least 40%; more preferably, by at least 50%; even morepreferably, by at least 50%; and most preferably, by at least 75%. Theproportion of proliferating cells may be measured by any reproduciblemeans of measurement. In a preferred aspect, the proportion ofproliferating cells is measured, for example, by quantifying the numberof dividing cells relative to the number of nondividing cells in atissue sample. In another preferred aspect, the proportion ofproliferating cells is equivalent to the mitotic index.

In another aspect, treating or preventing a cell proliferative disorderresults in a decrease in size of an area or zone of cellularproliferation. Preferably, after treatment, size of an area or zone ofcellular proliferation is reduced by at least 5% relative to its sizeprior to treatment; more preferably, reduced by at least 10%; morepreferably, reduced by at least 20%; more preferably, reduced by atleast 30%; more preferably, reduced by at least 40%; more preferably,reduced by at least 50%; even more preferably, reduced by at least 50%;and most preferably, reduced by at least 75%. Size of an area or zone ofcellular proliferation may be measured by any reproducible means ofmeasurement. In a preferred aspect, size of an area or zone of cellularproliferation may be measured as a diameter or width of an area or zoneof cellular proliferation.

In another aspect, treating or preventing a cell proliferative disorderresults in a decrease in the number or proportion of cells having anabnormal appearance or morphology. Preferably, after treatment, thenumber of cells having an abnormal morphology is reduced by at least 5%relative to its size prior to treatment; more preferably, reduced by atleast 10%; more preferably, reduced by at least 20%; more preferably,reduced by at least 30%; more preferably, reduced by at least 40%; morepreferably, reduced by at least 50%; even more preferably, reduced by atleast 50%; and most preferably, reduced by at least 75%. An abnormalcellular appearance or morphology may be measured by any reproduciblemeans of measurement. In one aspect, an abnormal cellular morphology ismeasured by microscopy, e.g., using an inverted tissue culturemicroscope. In one aspect, an abnormal cellular morphology takes theform of nuclear pleiomorphism.

As used herein, the term “selectively” means tending to occur at ahigher frequency in one population than in another population. In oneaspect, the compared populations are cell populations. In a preferredaspect, a compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, analog or derivative thereof, actsselectively on a cancer or precancerous cell but not on a normal cell.In another preferred aspect, a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof, acts selectively to modulate one molecular target(e.g., B-RAF). In another preferred aspect, the invention provides amethod for selectively inhibiting the activity of an enzyme, such as akinase. Preferably, an event occurs selectively in population A relativeto population B if it occurs greater than two times more frequently inpopulation A as compared to population B. More preferably, an eventoccurs selectively if it occurs greater than five times more frequentlyin population A. More preferably, an event occurs selectively if itoccurs greater than ten times more frequently in population A; morepreferably, greater than fifty times; even more preferably, greater than100 times; and most preferably, greater than 1000 times more frequentlyin population A as compared to population B. For example, cell deathwould be said to occur selectively in cancer cells if it occurredgreater than twice as frequently in cancer cells as compared to normalcells.

In a preferred aspect, a compound of the present invention or apharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof, modulates the activity of a molecular target (e.g.,B-RAF). In one aspect, modulating refers to stimulating or inhibiting anactivity of a molecular target. Preferably, a compound of the presentinvention modulates the activity of a molecular target if it stimulatesor inhibits the activity of the molecular target by at least 2-foldrelative to the activity of the molecular target under the sameconditions but lacking only the presence of said compound. Morepreferably, a compound of the present invention modulates the activityof a molecular target if it stimulates or inhibits the activity of themolecular target by at least 5-fold, at least 10-fold, at least 20-fold,at least 50-fold, at least 100-fold relative to the activity of themolecular target under the same conditions but lacking only the presenceof said compound. The activity of a molecular target may be measured byany reproducible means. The activity of a molecular target may bemeasured in vitro or in vivo. For example, the activity of a moleculartarget may be measured in vitro by an enzymatic activity assay or a DNAbinding assay, or the activity of a molecular target may be measured invivo by assaying for expression of a reporter gene.

In one aspect, a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof, does not significantly modulate the activity of amolecular target if the addition of the compound does not stimulate orinhibit the activity of the molecular target by greater than 10%relative to the activity of the molecular target under the sameconditions but lacking only the presence of said compound.

As used herein, the term “isozyme selective” means preferentialinhibition or stimulation of a first isoform of an enzyme in comparisonto a second isoform of an enzyme (e.g., preferential inhibition orstimulation of a kinase isozyme alpha in comparison to a kinase isozymebeta). Preferably, a compound of the present invention demonstrates aminimum of a four-fold differential, preferably a ten fold differential,more preferably a fifty fold differential, in the dosage required toachieve a biological effect. Preferably, a compound of the presentinvention demonstrates this differential across the range of inhibition,and the differential is exemplified at the IC₅₀, i.e., a 50% inhibition,for a molecular target of interest.

In a preferred embodiment, administering a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,analog or derivative thereof, to a cell or a subject in need thereofresults in modulation (i.e., stimulation or inhibition) of an activityof RAF. As used herein, an activity of RAF refers to any biologicalfunction or activity that is carried out by RAF. For example, a functionof RAF includes phosphorylation of downstream target proteins.

In a preferred embodiment, administering a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,analog or derivative thereof, to a cell or a subject in need thereofresults in modulation (i.e., stimulation or inhibition) of an activityof ERK 1 or ERK 2, or both. As used herein, an activity of ERK 1 or ERK2 refers to any biological function or activity that is carried out byERK 1 or ERK 2. For example, a function of ERK 1 or ERK 2 includesphosphorylation of downstream target proteins.

In one aspect, activating refers to placing a composition of matter(e.g., protein or nucleic acid) in a state suitable for carrying out adesired biological function. In one aspect, a composition of mattercapable of being activated also has an unactivated state. In one aspect,an activated composition of matter may have an inhibitory or stimulatorybiological function, or both.

In one aspect, elevation refers to an increase in a desired biologicalactivity of a composition of matter (e.g., a protein or a nucleic acid).In one aspect, elevation may occur through an increase in concentrationof a composition of matter.

As used herein, “a cell cycle checkpoint pathway” refers to abiochemical pathway that is involved in modulation of a cell cyclecheckpoint. A cell cycle checkpoint pathway may have stimulatory orinhibitory effects, or both, on one or more functions comprising a cellcycle checkpoint. A cell cycle checkpoint pathway is comprised of atleast two compositions of matter, preferably proteins, both of whichcontribute to modulation of a cell cycle checkpoint. A cell cyclecheckpoint pathway may be activated through an activation of one or moremembers of the cell cycle checkpoint pathway. Preferably, a cell cyclecheckpoint pathway is a biochemical signaling pathway.

As used herein, “cell cycle checkpoint regulator” refers to acomposition of matter that can function, at least in part, in modulationof a cell cycle checkpoint. A cell cycle checkpoint regulator may havestimulatory or inhibitory effects, or both, on one or more functionscomprising a cell cycle checkpoint. In one aspect, a cell cyclecheckpoint regulator is a protein. In another aspect, a cell cyclecheckpoint regulator is not a protein.

In one aspect, treating cancer or a cell proliferative disorder resultsin cell death, and preferably, cell death results in a decrease of atleast 10% in number of cells in a population. More preferably, celldeath means a decrease of at least 20%; more preferably, a decrease ofat least 30%; more preferably, a decrease of at least 40%; morepreferably, a decrease of at least 50%; most preferably, a decrease ofat least 75%. Number of cells in a population may be measured by anyreproducible means. In one aspect, number of cells in a population ismeasured by fluorescence activated cell sorting (FACS). In anotheraspect, number of cells in a population is measured byimmunofluorescence microscopy. In another aspect, number of cells in apopulation is measured by light microscopy. In another aspect, methodsof measuring cell death are as shown in Li et al, (2003) Proc Natl AcadSci USA. 100(5): 2674-8. In an aspect, cell death occurs by apoptosis.

In a preferred aspect, an effective amount of a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,analog or derivative thereof is not significantly cytotoxic to normalcells. A therapeutically effective amount of a compound is notsignificantly cytotoxic to normal cells if administration of thecompound in a therapeutically effective amount does not induce celldeath in greater than 10% of normal cells. A therapeutically effectiveamount of a compound does not significantly affect the viability ofnormal cells if administration of the compound in a therapeuticallyeffective amount does not induce cell death in greater than 10% ofnormal cells. In an aspect, cell death occurs by apoptosis.

In one aspect, contacting a cell with a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,analog or derivative thereof, induces or activates cell deathselectively in cancer cells. Preferably, administering to a subject inneed thereof a compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, analog or derivative thereof,induces or activates cell death selectively in cancer cells. In anotheraspect, contacting a cell with a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof, induces cell death selectively in one or more cellsaffected by a cell proliferative disorder. Preferably, administering toa subject in need thereof a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof, induces cell death selectively in one or more cellsaffected by a cell proliferative disorder. In a preferred aspect, thepresent invention relates to a method of treating or preventing cancerby administering a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof to a subject in need thereof, where administration ofthe compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, analog or derivative thereof results in oneor more of the following: accumulation of cells in G1 and/or S phase ofthe cell cycle, cytotoxicity via cell death in cancer cells without asignificant amount of cell death in normal cells, antitumor activity inanimals with a therapeutic index of at least 2, and activation of a cellcycle checkpoint. As used herein, “therapeutic index” is the maximumtolerated dose divided by the efficacious dose.

One skilled in the art may refer to general reference texts for detaileddescriptions of known techniques discussed herein or equivalenttechniques. These texts include Ausubel et al., Current Protocols inMolecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al.,Molecular Cloning, A Laboratory Manual (3d ed.), Cold Spring HarborPress, Cold Spring Harbor, N.Y. (2000); Coligan et al, Current Protocolsin Immunology, John Wiley & Sons, N.Y.; Enna et al, Current Protocols inPharmacology, John Wiley & Sons, N.Y.; Fingl et al, The PharmacologicalBasis of Therapeutics (1975), Remington's Pharmaceutical Sciences, MackPublishing Co., Easton, Pa., 18th edition (1990). These texts can, ofcourse, also be referred to in making or using an aspect of theinvention.

In additional aspects, a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof, may be administered in combination with a secondchemotherapeutic agent. The second chemotherapeutic agent can be ataxane, an aromatase inhibitor, an anthracycline, a microtubuletargeting drug, a topoisomerase poison drug, a targeted monoclonal orpolyconal antibody, an inhibitor of a molecular target or enzyme (e.g.,a kinase inhibitor), or a cytidine analogue drug. In preferred aspects,the chemotherapeutic agent can be, but not restricted to, tamoxifen,raloxifene, anastrozole, exemestane, letrozole, HERCEPTIN®(trastuzumab), GLEEVEC® (imatanib), TAXOL® (paclitaxel),cyclophosphamide, lovastatin, minosine, araC, 5-fluorouracil (5-FU),methotrexate (MTX), TAXOTERE® (docetaxel), ZOLADEX® (goserelin),vincristin, vinblastin, nocodazole, teniposide, etoposide, GEMZAR®(gemcitabine), epothilone, navelbine, camptothecin, daunonibicin,dactinomycin, mitoxantrone, amsacrine, doxorubicin (adriamycin),epirubicin or idarubicin or agents listed inwww.cancerorg/docroot/cdg/cdg_(—)0.asp. In another aspect, the secondchemotherapeutic agent can be a cytokine such as G-CSF (granulocytecolony stimulating factor). In another aspect, a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,analog or derivative thereof, may be administered in combination withradiation therapy. In yet another aspect, a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,analog or derivative thereof, may be administered in combination withstandard chemotherapy combinations such as, but not restricted to, CMF(cyclophosphamide, methotrexate and 5-fluorouracil), CAF(cyclophosphamide, adriamycin and 5-fluorouracil), AC (adriamycin andcyclophosphamide), FEC (5-fluorouracil, epirubicin, andcyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide, andpaclitaxel), or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil andprednisone).

A compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, analog or derivative thereof, can beincorporated into pharmaceutical compositions suitable foradministration. Such compositions typically comprise the compound (i.e.including the active compound), and a pharmaceutically acceptableexcipient or carrier. As used herein, “pharmaceutically acceptableexcipient” or “pharmaceutically acceptable carrier” is intended toinclude any and all solvents, dispersion media, coatings, antibacterialand antifungal agents, isotonic and absorption delaying agents, and thelike, compatible with pharmaceutical administration. Suitable carriersare described in the most recent edition of Remington's PharmaceuticalSciences, a standard reference text in the field. Preferred examples ofsuch carriers or diluents include, but are not limited to, water,saline, ringer's solutions, dextrose solution, and 5% human serumalbumin. Pharmaceutically acceptable carriers include solid carrierssuch as lactose, terra alba, sucrose, talc, gelatin, agar, pectin,acacia, magnesium stearate, stearic acid and the like. Exemplary liquidcarriers include syrup, peanut oil, olive oil, water and the like.Similarly, the carrier or diluent may include time-delay material knownin the art, such as glyceryl monostearate or glyceryl distearate, aloneor with a wax, ethylcellulose, hydroxypropylmethylcellulose,methylmethacrylate or the like. Other fillers, excipients, flavorants,and other additives such as are known in the art may also be included ina pharmaceutical composition according to this invention. Liposomes andnon-aqueous vehicles such as fixed oils may also be used. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active compound, use thereof in the compositionsis contemplated. Supplementary active compounds can also be incorporatedinto the compositions.

In one aspect, a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof, is administered in a suitable dosage form preparedby combining a therapeutically effective amount (e.g., an efficaciouslevel sufficient to achieve the desired therapeutic effect throughinhibition of tumor growth, killing of tumor cells, treatment orprevention of cell proliferative disorders, etc.) of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug,metabolite, analog or derivative thereof, (as an active ingredient) withstandard pharmaceutical carriers or diluents according to conventionalprocedures (i.e., by producing a pharmaceutical composition of theinvention). These procedures may involve mixing, granulating, andcompressing or dissolving the ingredients as appropriate to attain thedesired preparation.

4. The Pharmaceutical Compositions and Formulations

A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (topical), andtransmucosal administration. Solutions or suspensions used forparenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates, and agents for theadjustment of tonicity such as sodium chloride or dextrose. The pH canbe adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

A compound or pharmaceutical composition of the invention can beadministered to a subject in many of the well-known methods currentlyused for chemotherapeutic treatment. For example, for treatment ofcancers, a compound of the invention may be injected directly intotumors, injected into the blood stream or body cavities or taken orallyor applied through the skin with patches. The dose chosen should besufficient to constitute effective treatment but not so high as to causeunacceptable side effects. The state of the disease condition (e.g.,cancer, precancer, and the like) and the health of the patient shouldpreferably be closely monitored during and for a reasonable period aftertreatment.

The term “therapeutically effective amount,” as used herein, refers toan amount of a pharmaceutical agent to treat, ameliorate, or prevent anidentified disease or condition, or to exhibit a detectable therapeuticor inhibitory effect. The effect can be detected by any assay methodknown in the art. The precise effective amount for a subject will dependupon the subject's body weight, size, and health; the nature and extentof the condition; and the therapeutic or combination of therapeuticsselected for administration. Therapeutically effective amounts for agiven situation can be determined by routine experimentation that iswithin the skill and judgment of the clinician. In a preferred aspect,the disease or condition to be treated is cancer. In another aspect, thedisease or condition to be treated is a cell proliferative disorder.

For any compound, the therapeutically effective amount can be estimatedinitially either in cell culture assays, e.g., of neoplastic cells, orin animal models, usually rats, mice, rabbits, dogs, or pigs. The animalmodel may also be used to determine the appropriate concentration rangeand route of administration. Such information can then be used todetermine useful doses and routes for administration in humans.Therapeutic/prophylactic efficacy and toxicity may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., ED₅₀ (the dose therapeutically effective in 50% of thepopulation) and LD₅₀ (the dose lethal to 50% of the population). Thedose ratio between toxic and therapeutic effects is the therapeuticindex, and it can be expressed as the ratio, LD₅₀/ED₅₀. Pharmaceuticalcompositions that exhibit large therapeutic indices are preferred. Thedosage may vary within this range depending upon the dosage formemployed, sensitivity of the patient and the route of administration.

Dosage and administration are adjusted to provide sufficient levels ofthe active agent(s) or to maintain the desired effect. Factors which maybe taken into account include the severity of the disease state, generalhealth of the subject, age, weight, and gender of the subject, diet,time and frequency of administration, drug combination(s), reactionsensitivities, and tolerance/response to therapy. Long-actingpharmaceutical compositions may be administered every 3 to 4 days, everyweek, or once every two weeks depending on half-life and clearance rateof the particular formulation.

The pharmaceutical compositions containing active compounds of thepresent invention may be manufactured in a manner that is generallyknown, e.g., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping, orlyophilizing processes. Pharmaceutical compositions may be formulated ina conventional manner using one or more pharmaceutically acceptablecarriers comprising excipients and/or auxiliaries that facilitateprocessing of the active compounds into preparations that can be usedpharmaceutically. Of course, the appropriate formulation is dependentupon the route of administration chosen.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringeability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as manitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle that contains abasic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation are vacuum dryingand freeze-drying that yields a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral compositions generally include an inert diluent or an ediblepharmaceutically acceptable carrier. They can be enclosed in gelatincapsules or compressed into tablets. For the purpose of oral therapeuticadministration, the active compound can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash,wherein the compound in the fluid carrier is applied orally and swishedand expectorated or swallowed. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition. The tablets, pills, capsules, troches and the like cancontain any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate or Sterotes; a glidant such as colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; or a flavoringagent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in theform of an aerosol spray from pressured container or dispenser, whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

In one aspect, the active compounds are prepared with pharmaceuticallyacceptable carriers that will protect the compound against rapidelimination from the body, such as a controlled release formulation,including implants and microencapsulated delivery systems.Biodegradable, biocompatible polymers can be used, such as ethylenevinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, and polylactic acid. Methods for preparation of suchformulations will be apparent to those skilled in the art. The materialscan also be obtained commercially from Alza Corporation and NovaPharmaceuticals, Inc. Liposomal suspensions (including liposomestargeted to infected cells with monoclonal antibodies to viral antigens)can also be used as pharmaceutically acceptable carriers. These can beprepared according to methods known to those skilled in the art forexample, as described in U.S. Pat. No. 4,522,811.

It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved.

In therapeutic applications, the dosages of the pharmaceuticalcompositions used in accordance with the invention vary depending on theagent, the age, weight, and clinical condition of the recipient patient,and the experience and judgment of the clinician or practitioneradministering the therapy, among other factors affecting the selecteddosage. Generally, the dose should be sufficient to result in slowing,and preferably regressing, the growth of the tumors and also preferablycausing complete regression of the cancer. Dosages can range from about0.01 mg/kg per day to about 3000 mg/kg per day. In preferred aspects,dosages can range from about 1 mg/kg per day to about 1000 mg/kg perday. In an aspect, the dose will be in the range of about 0.1 mg/day toabout 50 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day toabout 10 g/day; about 0.1 mg to about 3 g/day; or about 0.1 mg to about1 g/day, in single, divided, or continuous doses (which dose may beadjusted for the patient's weight in kg, body surface area in m², andage in years). An effective amount of a pharmaceutical agent is thatwhich provides an objectively identifiable improvement as noted by theclinician or other qualified observer. For example, regression of atumor in a patient may be measured with reference to the diameter of atumor. Decrease in the diameter of a tumor indicates regression.Regression is also indicated by failure of tumors to reoccur aftertreatment has stopped. As used herein, the term “dosage effectivemanner” refers to amount of an active compound to produce the desiredbiological effect in a subject or cell.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

All patents, patent applications and references cited herein areincorporated by reference herein in their entirety.

EXAMPLES

Examples are provided below to further illustrate different features ofthe present invention. The examples also illustrate useful methodologyfor practicing the invention. These examples do not limit the claimedinvention.

Example 1 Preparation of3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol1a: Preparation of 6-(3-methoxyphenyl)-imidazo[2,1-b]thiazole

To a mixture of 2-aminothiazole (2.7 g, 26.7 mmol) and2-bromo-3′-methoxyacetophenone (6.0 g, 0.0262 mol) was added absoluteethanol (100 ml). The reaction was allowed to reflux with vigorousstirring for 18 hours (checked by HPLC). The reaction mixture wasreduced to half its original volume in vacuo. The remaining liquid waspoured onto ice and the solution made basic by the addition of ammoniumhydroxide solution (30%). The resulting fine solid was filtered andwashed with water resulting in a dark yellow solid product. The solidproduct was dried in a vacuum oven at 50° C. to provide6-(3-methoxyphenyl)-imidazo[2,1-b]thiazole (5.0 g, 81%). 400 MHz ¹H NMR(DMSO-d₆) δ 8.18 (s, 1H), 7.88 (d, J=4.4 Hz, 1H), 7.36-7.42 (m, 2H),7.28 (t, J=8.1 Hz, 1H), 7.22 (d, J=4.4 Hz, 1H), 6.82 (ddd, J=8.1, 2.6,1.1 Hz, 1H), 3.80 (s, 3H). LCMS: 231 [M+H].

1b: Preparation of1-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone

To a mixture of 6-(3-methoxyphenyl)-imidazo[2,1-b]thiazole (14.3 g, 62mmol) and acetic anhydride (250 ml) was added 1 ml of concentratedsulfuric acid. The reaction mixture was heated at 140° C. for 4 hours.The reaction mixture was then poured onto 500 ml of ice, and dilutedwith 500 ml of water and the resulting mixture was extracted three timeswith 300 ml each of ethyl acetate. The combined extracts were washedwith three portions of 100 ml of water and one portion of 200 ml ofsaturated aqueous sodium chloride solution. The organic phase was driedwith magnesium sulfate, filtered and concentrated in vacuo, to give abrown oil (17.95 g). The product,-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone, was useddirectly in the next step. 400 MHz ¹H NMR (DMSO-d₆) δ 8.43 (d, J=4.4 Hz,1H), 7.55 (d, J=4.4 Hz, 1H), 7.42 (t, J=8.2 Hz, 1H), 7.16-7.2 (m, 2H),7.04-7.1 (m, 1H), 3.81 (s, 3H), 2.13 (s, 3H). LCMS: 273 [M+H].

1c: Preparation of3-(dimethylamino)-1-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]prop-2-en-1-one

A 100 ml round bottom flask was charged with the1-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone (17.95 g,62 mmol) and dimethylformamide dimethylacetal (120 ml). The mixture wasrefluxed for 72 hours and then cooled to room temperature. The mixturewas concentrated in vacuo and the residue was purified by flashchromatography (ethyl acetate), giving a pale yellow solid (16.82 g).300 MHz ¹H NMR (DMSO-d₆) δ: 8.40 (d, J=4.4 Hz, 1H), 7.59 (d, J=12.5 Hz,1H), 7.41 (d, J=4.4 Hz, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.17-7.21 (m, 2H),6.99-7.03 (m, 1H), 5.15 (d, J=12.5 Hz, 1H), 3.79 (s, 3H), 3.04 (s, 3H),2.44 (s, 3H).

1d: Preparation of tert-butyl(3R)-3-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylatehydrochloride

To a mixture of tert-butyl (3R)-3-aminopiperidine-1-carboxylate (10 g,49.9 mmol) and pyrazole carboxamidine hydrochloride (7.31 g, 49.9 mmol)was added Hunig's base (8.72 ml, 49.9 mmol) and DMF (30 ml). Thereaction was heated at 70° C. for 18 hours. The reaction was then cooledto room temperature and quenched by adding 700 ml of diethyl ether andstirring at room temperature for 24 hours. Product separated out as awhite solid, which was filtered, washed, and dried (13 g, 94%). 400 MHz¹H NMR (DMSO-d₆) δ: 7.67 (d, J=8.8 HZ, 1H), 6.9-7.6 (br. s, 4H), 3.55(br.s, 2H), 2.8-3.6 (m, 4H), 2.8-2.9 (m, 1H), 1.6-1.7 (m, 1H), 1.39 (s,9H), 1.2-1.3 (m, 1H). LCMS: 243 [M+H].

1e: Preparation of tert-butyl(3R)-3-({4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate

A mixture of3-(dimethylamino)-1-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]prop-2-en-1-one(5.0 g, 15.3 mmol) and tert-butyl(3R)-3-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylatehydrochloride (5.28 g, 18.95 mmol) was diluted with 60 ml of absoluteethanol and treated with 1.15 eq. of a 21% w/w solution of sodiumethoxide in ethanol (6.56 ml) to form a reaction mixture. The reactionmixture was heated to reflux for 24 hours. Volatiles were removed invacuo and the residue was taken up in 250 ml of ethyl acetate and 250 mlof water. The phases were separated and the aqueous phase was extractedwith 250 ml of ethyl acetate. The combined organic extracts were washedwith 250 ml each of water, and then with a saturated sodium chloridesolution (250 ml). The organic phase was dried with magnesium sulfate,filtered and concentrated in vacuo, to give a yellow oil. The productwas purified by flash chromatography on silica gel (ethylacetate/hexanes, 50%) to yield 7.2 g of a pale yellow solid (93%). 300MHz ¹H NMR (DMSO-d₆ at 80° C.) δ: 8.69 (d, J=3.5 Hz, 1H), 8.10 (d, J=5.3Hz, 1H), 7.32-7.41 (m, 2H), 7.12-7.18 (m, 2H), 6.91-7.02 (m, 2H), 6.41(d, J=5.3 Hz, 1H), 3.94 (br. d, J=7.0, 1H), 3.74-3.88 (m, 1H), 3.78 (s,3H), 3.67 (br. d, J=13.2, 1H), 2.86-3.02 (m, 2H), 1.90-2.06 (m, 1H),1.70-1.84 (m, 1H), 1.38-1.64 (m, 2H), 1.34 (s, 9H). LCMS: 507 [M+H].

1f: Preparation of4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-aminehydrochloride

The tert-butyl(3R)-3-({4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate(21 g, 41.5 mmol) was dissolved in 250 ml of dioxane and treated with 75ml of anhydrous a four molar HCl in dioxane at room temperature. Thereaction mixture was stirred at room temperature for three hours. Themixture was then diluted with 350 ml of ether and stirred until productseparated as a solid. Solid product was filtered and washed with ether.The solid was dissolved in MeOH (200 ml) and concentrated to dryness(this was done twice). The product was dried at high vacuum to yield20.275 g of yellow solid (tris HCl salt) (90%). M.p.=220-225° C.; 300MHz ¹H NMR (DMSO-d₆ at 80° C.) δ: 9.6-9.3 (br. s, 2H), 8.9-8.4 (br. s,2H), 8.82 (s, 1H), 8.11 (d, J=5.8 Hz, 1H), 7.50 (d, J=4.7 Hz, 1H), 7.39(t, J=7.98 Hz, 1H), 7.2-7.1 (m, 2H), 7.08-7.0 (m, 1H), 6.49 (d, J=5.8Hz, 1H), 4.4-4.3 (m, 1H), 3.79 (s, 3H), 3.39 (d, J=10.2 Hz, 1H), 3.16(br. s, 1H), 3.05-2.7 (m, 2H), 2.2-1.6 (m, 3H), 1.55-1.2 (m, 1H). LCMS:407 [M+H]; calc. for C₂₁H₂₂N₆OS 3.3 HCl 0.05 dioxane 0.3 methanol: C,47.75; H, 5.01; N, 15.54. found C, 47.73; H, 5.26; N, 15.55.

1g: Preparation ofN-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine

The4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-aminehydrochloride (6.81 g, 14.2 mmol) in methylene chloride (DCM) (60 ml)was cooled to 0° C. and was treated with Hunig's base (9.9 ml, 56.8mmol). The mixture was kept at 0° C. for 30 minutes then the4-chlorophenylsulfonyl chloride (3.3 g, 15.6 mmol) was added. Thereaction mixture was stirred at room temperature overnight. The mixturewas diluted with methylene chloride (100 ml) and was washed water (100ml) and a saturated aqueous sodium chloride solution (100 ml). Theorganic phase was dried over sodium sulfate and concentrated in vacuo.The crude product was purified by flash chromatography using a gradient(ethyl acetate/hexanes, 40-100%), affording 6.98 g (85%) of the titlecompound as a pale yellow solid. 400 MHz ¹H NMR (DMSO-d₆ at 60° C.) δ:8.42 (br. s, 1H), 8.12 (d, J=5.1 Hz, 1H), 7.8-7.75 (m, 2H), 7.7-7.65 (m,2H), 7.43-7.39 (m, 10H), 7.36 (d, J=7.8 Hz, 1H), 7.18-7.1 (m, 2H),7.05-6.98 (m, 1H), 6.42 (d, J=5.1 Hz, 1H), 4.0-3.9 (m, 1H), 3.78 (s,3H), 3.74 (d, J=11.7 Hz, 1H), 3.48 (d, J=11.7 Hz, 1H), 2.5-2.4 (m, 1H),2.33 (t, J=5.3 Hz, 1H), 1.95-1.8 (m, 2H), 1.65-1.5 (m, 1H), 1.45-1.4 (m,1H). LCMS: 581 [M+H].

1h: Preparation of3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol

TheN-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-methoxy-phenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine(6.98 g, 12.03 mmol) in methylene chloride (100 ml) was cooled to −78°C. and slowly treated with 1 molar solution of boron tribromide inmethylene chloride (65 ml). The reaction mixture was kept at −78° C. forone hour then was allowed to warm to room temperature for two hours. Themixture was quenched by the addition of methanol (25 ml) at 0° C. andwas stirred at room temperature for an additional hour. The mixture wasdiluted with methylene chloride (500 ml) and washed with three portionsof 100 ml of saturated sodium bicarbonate solution, two portions of 100ml of water and two portions of 100 ml of saturated sodium chloridesolution. The organic phase was dried over sodium sulfate andconcentrated in vacuo, giving a yellow foam. The crude product wasre-crystallized from methanol as a yellow solid (4.85 g, 71%).M.p.=174-177° C. 400 MHz ¹H NMR (DMSO-d₆ at 60° C.) δ: 9.4 (br. s, 1H),8.70 (br. s, 1H), 8.12 (d, J=5.5 Hz, 1H), 7.8-7.7 (m, 2H), 7.7-7.65 (m,2H), 7.40 (d, J=4.7 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.15 (d, J=7.4 Hz,1H), 7.0-6.95 (m, 1H), 6.85-6.8 (m, 1H), 6.44 (d, J=5.5 Hz, 1H), 3.95(br. s, 1H), 3.72 (dd, J=10.6 3.1 Hz, 1H), 3.40 (m, 10H), 2.5-2.4 (m,1H), 2.35 (t, J=10.2 Hz, 1H), 2.0-1.8 (m, 2H), 1.65-1.5 (m, 1H),1.46-1.32 (m, 1H). LCMS: 567 [M+H]. Calc. for C₂₆H₂₃N₆O₃S₂Cl 0.5 water1.0 methanol: C, 53.33; H, 4.64; N, 13.82. found C, 53.32; H, 4.64; N,13.82.

Example 2 Preparation of 2-amino-oxazole

To a solution of cyanamide (19.8 ml of 50% w/w in water, 0.25 mol) inTHF (60 ml) was added the hydroxyacetaldehyde (15 g, 0.25 mol) in 24 mlof water. The reaction mixture was treated at 0° C. with a solution ofsodium hydroxide 2 M (25.2 ml, 0.05 mol). The mixture was allowed towarm to room temperature and stirred for 24 hrs. The volatiles wereremoved in vacuo (THF) and the remaining aqueous solution was extractedwith four portions of 200 ml of ethyl acetate. The organic extracts weredried over sodium sulfate and concentrated in vacuo, yielding 14.968 g(71.3%) of a white solid. 400 MHz ¹H NMR (CDCl₃) δ: 7.13 (s, 1H), 6.74(s, 1H), 5.26 (br. s, 2H). Calc. for C₃H₄N₂O: C, 42.86; H, 4.80; N,33.32. found C, 43.01; H, 4.87; N, 33.11.

Example 3 Preparation ofN-[4-(dimethylamino)phenyl]-4-({4-[6-(4-fluorophenyl)-imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxamide3a: Preparation of1-(4-fluorophenyl)-2-(2-imino-1,3-oxazol-3(2H)-yl)ethanone hydrobromide

A solution of 2-amino-oxazole (14.9 g, 0.179 mol) in acetonitrile (100ml) was slowly added over a period of 20 minutes to a solution of2-bromo-1-(4-fluorophenyl)ethanone (57.6 g, 0.36 mol) in THF (150 ml).The reaction mixture was stirred at room temperature for 24 hrs thencooled to 0° C. A precipitate formed and was filtered off. The solid waswashed with three portions of 30 ml of cold acetonitrile and dried at50° C. under vacuum, yielding 38.75 g (72%) of an off-white solid.M.p.=218-221° C.; 300 MHz ¹H NMR (DMSO-d₆) δ: 9.80 (br. s, 1H),8.16-8.11 (m, 2H), 8.00 (s, 1H), 7.62 (s, 1H), 7.52-7.46 (m, 2H), 5.80(s, 2H); LCMS: 221 [M+H]. Calc. for C, 1H₉N₂O₂F 1.05 HBr, 0.14 ACN: C,43.58; H, 3.39; N, 9.64. found C, 43.63; H, 3.38; N, 9.65.

3b: Preparation of 6-(4-fluorophenyl)-imidazo[2,1-b]oxazole

The 1-(4-fluorophenyl)-2-(2-iminooxazol-3-yl)-ethanone hydrobromide salt(10.0 g, 0.32 mol) was introduced in a two-neck flask, fitted with acondenser, and flushed with nitrogen. Anhydrous toluene (100 ml) wasadded and the mixture was cooled to −10° C. TiCl₄ (17.5 ml, 0.16 mol)was added over a period of 30 minutes. The reaction becomes deep red anda dark precipitate was formed. The reaction mixture was allowed to warmto room temperature. The mixture was then brought to reflux and kept areflux for 5.5 hrs. The reaction mixture was cooled to room temperatureovernight. The toluene was decanted and iced water (60 ml) was added tothe residue (caution!), which turned from dark brown to beige. Theresulting suspension was transferred to a large beaker and treated withsaturated aqueous sodium carbonate solution until pH 8. A saturatedaqueous sodium chloride solution was added (200 ml), followed by 600 mlof ethyl acetate and the mixture was stirred vigorously for one hour.The organic phase was separated and the aqueous phase was furtherextracted with two portions of 600 ml of ethyl acetate. The organicextracts were dried over sodium sulfate and concentrated in vacuo,yielding 6.84 g of a pale yellow solid. 400 MHz ¹H NMR (CDCl₃) δ:7.78-7.72 (m, 2H), 7.37 (d, J=1.8 Hz, 1), 7.31 (d, J=1.8 Hz, 1), 7.24(s, 1H), 7.10-7.00 (m, 2H).

3c: Preparation of1-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]ethanone

A solution of 6-(4-fluorophenyl)-imidazo[2,1-b]oxazole (2.5 g, 0.0124mol) in acetic anhydride (60 ml) was heated to 140° C. and then treatedwith concentrated sulfuric acid (5 drops). After 15 minute at thattemperature, HPLC showed clean conversion and the reaction mixture wasquenched by the addition of ice cold water (150 ml). The mixture wasextracted with ethyl acetate (3×150 ml). The combined extracts werewashed with a saturated aqueous sodium chloride solution (300 ml), driedover magnesium sulfate and concentrated in vacuo as a brown solid.Trituration from a mixture of hexanes/ethyl:acetate (1:1) provided 2.2 g(72.6%) of a pale yellow solid. M.p.=173° C.; 300 MHz ¹H NMR (DMSO-d₆) δ8.25-8.19 (m, 2H), 7.75-7.68 (m, 2H), 7.35-7.25 (m, 2H), 2.15 (s, 3H).LCMS: 245 [M+H].

3d: Preparation of3-(dimethylamino)-1-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]prop-2-en-1-one

A solution of1-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]ethanone (0.0374 g,0.000153 mol) in N,N-dimethylformamide dimethyl acetal (3.0 ml) washeated to 100° C. for 24 hrs. HPLC showed complete consumption of thestarting material. The volatiles were removed in vacuo, yielding a brownsolid (0.046 g, quantitative). M.p.=187-189° C.; 300 MHz ¹H NMR (CDCl₃)δ8.03 (s, 1H), 7.72-7.64 (m, 3H), 7.46 (s, 1H), 7.13-7.10 (m, 2H), 5.19(d, J=12.5 Hz, 1H), 3.07 (bs, 3H), 2.55 (bs, 31H). LCMS: 300 [M+H].Calc. for C₁₆H₁₄FN₃O₂: C, 64.21; H, 4.71; N, 14.04. found C, 64.22; H,4.31; N, 14.10.

3e: Preparation of tert-butyl4-{[amino(imino)methyl]amino}piperidine-1-carboxylate hydrochloride

To a mixture of tert-butyl 4-aminopiperidine-1-carboxylate (8.93 g, 44.6mmol) and pyrazole carbox-amidine hydrochloride (6.536 g, 44.6 mmol) wasadded Hunig's base (7.77 ml, 44.6 mmol) and DMF (25 ml). The reactionwas heated at 60° C. for 15 hours. The reaction was then cooled to roomtemperature and quenched by adding 400 ml of diethyl ether and stirringat room temperature for 2 hours. Product separated out as a white solid,which was filtered, washed and dried (10.9 g, 88%). M.p.=169-172° C.;400 MHz ¹H NMR (DMSO-d₆) δ: 8.09 (d, J=8.8 HZ, 1H), 6.9-7.9 (br. s, 3H),3.83 (d, J=13.6 Hz, 2H), 3.63 (m, 1H), 2.88 (m, 2H), 1.80 (m, 2H), 1.40(s, 9H), 1.25 (m, 2H); LCMS: 243 [M+H]; calc. for C₁₁H₂₂N₄O₂ 1.06 HCl0.2H₂O: C, 46.39; H, 8.31; N, 19.68. found C, 46.43; H, 8.31; N, 20.68.

3f: Preparation of tert-butyl4-({4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate

A mixture of3-(dimethylamino)-1-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]prop-2-en-1-one(4.24 g, 14.2 mmol) and tert-butyl4-{[amino(imino)methyl]amino}-piperidine-1-carboxylate hydrochloride(5.92 g, 21.2 mmol) was diluted with 40 ml of absolute ethanol andtreated with 1.35 eq. of a 21% w/w solution of sodium ethoxide inethanol (7.2 ml) to form a reaction mixture. The reaction mixture washeated to reflux for 15 hours. Volatiles were removed in vacuo and theresidue was taken up in 200 ml of ethyl acetate, washed twice with 100ml each of water, and then with a saturated sodium chloride solution(100 ml). The organic phase was dried with magnesium sulfate, filteredand concentrated in vacuo, to give a brown solid. The product waspurified by flash chromatography on silica gel (gradient 50%-75% ethylacetate/hexanes) to yield 4.436 g of a tan solid (65%). M.p.=175° C.;300 MHz ¹H NMR (CDCl₃) δ: 8.06 (s, 1H), 8.04 (s, 1H), 7.65-7.60 (m, 2H),7.48 (d, J=1.6 Hz, 1H), 7.17-7.13 (m, 2H), 6.52 (d, J=5.6 Hz, 1H), 5.1(br. s, 1H), 4.2-3.9 (m, 3H), 2.2-2.0 9M, 2H), 16.-1.4 (m, 4H), 1.48 (s,9H). LCMS: 479 [M+H]; calc. for C₂₅H₂₇FN₆O₃ 0.25H₂O: C, 62.11; H, 5.74;N, 17.39. found C, 62.43; H, 5.37; N, 17.35.

3g: Preparation of4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-piperidin-4-ylpyrimidin-2-aminehydrochloride

A solution of tert-butyl4-({4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate(3.2 g, 0.0067 mol) in dioxane (35 ml) was treated with HCl 4 M indioxane (5 ml). The reaction mixture was stirred at room temperature for4 hrs. The volatiles were removed in vacuo, giving 2.951 g (98%) of ayellow solid. M.p.=217-220° C.; 300 MHz ¹H NMR (DMSO-d₆) δ: 9.55-9.25(br. m, 2H), 9.03 (br. s, 1H), 8.31 (s, 1H), 8.06 (br., 1H), 7.67 (t,J=7.1 Hz, 2H), 7.38 (t, J=8.8 Hz, 2H), 6.50 (d, J=6.0 Hz, 1H), 4.22 (brs, 1H), 3.5-3.3 (m, 2H), 3.25-2.9 (m, 2H), 2.16 (br. d, J=11.5 Hz, 2H),2.0-1.8 (m, 2H). LCMS: 379 [M+H]; calc. for C₂₀H₁₉FN₆O 3.0 HCl 0.3dioxane: C, 49.47; H, 4.78; N, 16.34. found C, 49.30; H, 4.77; N, 16.51.

3h: Preparation ofN-[4-(dimethylamino)phenyl]-4-({4-[6-(4-fluorophenyl)-imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxamide

The4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-piperidin-4-ylpyrimidin-2-amine(bis HCl salt) (100 mg, 0.222 mmol) in tetrahydrofuran (5 ml) wastreated with Hunig's base (240 ul), followed by 4-dimethylaminophenylwasocyanate (44 mg). The reaction mixture was stirred at roomtemperature for 18 hours. The mixture was quenched by the addition ofwater (15 ml) and extracted with ethyl acetate (10 ml). The organicphase was washed with one portion of 10 ml of saturated sodium chloridesolution, dried over sodium sulfate and concentrated in vacuo. Theproduct was purified by trituration in ether, giving 116 mg of a paleyellow solid (97%). M.p.=225-227° C. 400 MHz ¹H NMR (DMSO-d₆) δ: 8.73(br. s, 1H), 8.24 (s, 1H), 8.18 (br. s, 1H), 8.10 (d, J=5.5 Hz, 1H),7.67-7.61 (m, 2H), 7.38-7.29 (m, 2H), 7.26-7.19 (m, 2H), 6.70-6.61 (m,2H), 6.35 (br. s, 1H), 4.08 (d, J=13.3 Hz, 2H), 4.00-3.90 (m, 1H), 2.93(t, J=1.5 Hz, 2H), 2.82 (s, 6H), 1.93 (d, J=10.5 Hz, 2H), 1.50-1.35 (m,2H). LCMS: 541 [M+H]. Calc. for C₂₉H₂₉N₈O₂F 0.35 ether: C, 64.45; H,5.78; N, 19.78. found C, 64.41; H, 5.58; N, 19.79.

Example 4 Preparation of4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-[1-(4-methoxybenzoyl)piperidin-4-yl]pyrimidin-2-amine

The4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-piperidin-4-ylpyrimidin-2-amine(his HCl salt) (100 mg, 0.222 mmol) in dichloromethane (5 ml) wastreated with triethylamine (500 ul). The mixture was cooled to 0° C. andtreated with 4-methoxy benzoyl chloride (36 mg, 0.2 mmole). The reactionmixture was stirred at room temperature for 18 hours. The mixture wasdiluted with dichloromethane (10 ml) and washed with a soln. of sodiumbicarbonate (3×15 ml) and water (15 ml). The organic phase was washedwith one portion of 10 ml of saturated sodium chloride solution, driedover sodium sulfate and concentrated in vacuo. The product was purifiedby trituration in ether, giving 75 mg of a pale yellow solid (70%).M.p.=196-197° C. 400 MHz ¹H NMR (CDCl₃) δ: 8.06-8.02 (m, 2H), 7.65-7.58(m, 2H), 7.49 (d, J=1.6 Hz, 1H), 7.44-7.38 (m, 2H), 7.17-7.11 (m, 2H),6.95-6.90 (m, 2H), 6.54 (d, J=5.5 Hz, 1H), 4.20-4.10 (m, 1H), 3.84 (s,3H), 3.30-3.12 (m, 2H), 2.25-2.10 (m, 2H), 1.85-1.50 (m, 4H). LCMS: 513[M+H]. Calc. for C₂₈H₂₅N₆O₃F 0.03 ether 0.52 water: C, 64.38; H, 5.07;N, 16.03. found C, 64.43; H, 5.01; N, 16.04.

Example 5 Preparation ofN-{2-[4-({4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]-2-oxoethyl}acetamide

The4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-piperidin-4-ylpyrimidin-2-amine(bis HCl salt) (100 mg, 0.222 mmol) in dimethylformamide (4 ml) wastreated with triethylamine (220 ul) and stirred until all solidsdissolve. The mixture was treated sequentially with the acetamidoglycine (26 mg), HBTU (84 mg) and DMAP (27 mg). The reaction mixture wasstirred at room temperature for 15 hours. The mixture was partitionedinto ethyl acetate (10 ml) and water (10 ml). The phases were separatedand the organic phase was washed with a saturated sodium carbonatesolution (10 ml), water (10 ml) and a saturated sodium chloride solution(10 ml). The organic phase was dried over sodium sulfate andconcentrated in vacuo. The crude product was purified by preparativechromatography plate (15% methanol/ethyl acetate), giving 78 mg of apale yellow solid (74%). M.p.=235-237° C. 400 MHz ¹H NMR (DMSO-d₆) δ:8.73 (br. s, 1H), 8.18 (br. s, 1H), 8.10 (d, J=5.5 Hz, 1H), 7.98 (t,J=5.7 Hz, 1H), 7.66-7.6 (m, 2H), 7.38-7.28 (m, 3H), 6.36 (br. s, 1H),4.26 (d, J=13.3 Hz, 1H), 4.05-3.87 (m, 3H), 3.82 (d, J=13.3 Hz, 1H),3.15 (t, J=11.5 Hz, 1H), 2.83 (t, J=11.5 Hz, 1H), 2.0-1.9 (m, 2H), 1.87(s, 3H), 1.5-1.2 (m, 2H). LCMS: 478 [M+H]. Calc. for C₂₄H₂₄N₇O₃F 0.44water: C, 59.38, H, 5.17; N, 20.20. found C, 59.38; H, 4.93; N, 20.47.

Example 6 Preparation ofN-[1-(4-fluorobenzyl)piperidin-3-yl]-4-[6-(4-fluorophenyl)-imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine

The racemic4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N—[piperidin-3-yl]pyrimidin-2-aminehydrochloride (70 mg g, 0.15 mmol) was dissolved in a 80/20 mixture ofDCE and DMF (1.2 ml) and treated with three equivalent of triethylamine(63 uL). The 4-fluorobenzaldehyde (19 mg, 0.15 mmol) was added, followedby a 0.2 M solution of Me₄NBH(OAc)₃ in 80/20 DCE/DMF (1.2 ml). Themixture was stirred at room temperature for 18 hours. The mixture waswashed with a 1N sodium hydroxide solution (2 ml). Concentration invacuo followed by purification on reverse phase HPLC provides the titlecompound as a pale yellow solid (42.4 mg, 56%). M.p.=131-133° C. 400 MHz¹H NMR (DMSO-d₆) δ: 8.73 (br. s, 1H), 8.06 (d, J=5.1 Hz, 1H), 7.64-7.58(m, 2H), 7.44 (d, J=4.7 Hz, 1H), 7.35-7.31 (m, 2H), 7.30-7.23 (m, 2H),7.07 (t, J=8.8 Hz, 2H), 7.00 (br. s, 1H), 6.29 (d, J=5.1 Hz, 1H),4.00-3.90 (m, 1H), 3.49 (s, 2H), 2.96-2.90 (m, 1H), 2.69-2.62 (m, 1H),2.08-1.94 (m, 2H), 1.93-1.85 (m, 1H), 1.76-1.67 (m, 1H), 1.61-1.48 (m,1H), 1.42-1.30 (m, 1H). LCMS: 503 [M+H].

Example 7 Preparation ofN˜1˜-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)glycinamide7a: Preparation of4-[6-(3-aminophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}pyrimidin-2-amine

N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-nitrophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine(1.05 g, 1.76 mmol) was dissolved in ethanol 95% (10 ml) and water (2.5ml). The solution was treated with irn powder (1 g, 17.6 mmol) andconcentrated HCl (200 uL). The reaction mixture was stirred at 100° C.for one hour. The mixture was cooled down and diluted with ethanol (100ml). The heterogenous mixture was filtered over Celite and the volatileswere removed in vacuo. The residue was taken up in EtOAc (150 ml) andthe organic phase was washed with a saturated aqueous NaHCO₃ solution(2×100 ml), water (100 ml) and a saturated aqueous NaCl solution (100ml). After drying over sodium sulfate and concentration, the solid wastriturated in ether, giving the title compound as a yellow powder, 0.835g (84%). M.p.=226-228° C. 400 MHz ¹H NMR (DMSO-d₆) δ: 8.73 (br. s, 1H),8.10 (d, J=5.6 Hz, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.67 (d, J=8.5 Hz, 2H),7.36 (d, J=4.4 Hz, 1H), 7.09 (t, J=7.7 Hz, 1H), 7.02 (d, J=7.3 Hz, 1H),6.81 (s, 1H), 6.69 (d, J=7.6 Hz, 1H), 6.65 (d, J=7.9 Hz, 1H), 6.49 (d,J=5.3 Hz, 1H), 5.01 (br. s, 2H), 4.02-3.88 (m, 1H), 3.73 (dd, J=11.1,3.5 Hz, 1H), 3.47 (d, J=11.7 Hz, 1H), 2.60-2.46 (m, 1H), 2.39 (t, J=10.2Hz, 1H), 1.98-1.80 (m, 2H), 1.68-1.51 (m, 1H), 1.47-1.32 (m, 1H). LCMS:566 [M+H]. Calc. for C₂₆H₂₄N₇O₂S₂Cl: C, 55.16; H, 4.27; N, 17.32. foundC, 54.98; H, 3.85; N, 17.23.

7b: Preparation of tert-butyl{2-[(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)amino]-2-oxoethyl}carbamate

The4-[6-(3-aminophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-chlorophenyl)-sulfonyl]piperidin-3-yl}pyrimidin-2-amine(0.1 g, 0.177 mmol) and N-(tert-butoxycarbonyl)glycine (34 mg, 0.194mmol) were dissolved in DCM (5 ml) and treated with Hunig's base (92 uL,0.53 mmol) and 2-chloro-1,3-dimethyl-1H-imidazol-3-ium chloride (33 mg,0.194 mmol). The mixture was kept at room temperature for 90 minutesthen was diluted with DCM (10 ml). The organic phase was washed withwater (2×10 ml) and with an aqueous sodium chloride solution (10 ml).The organic phase was dried over sodium sulfate and concentrated invacuo, giving a yellow oil. The product was purified by flashchromatography (gradient 70%-100% EtoAc/hexanes), affording the titlecompound as a pale yellow solid (71 mg). 400 MHz ¹H NMR (DMSO-d₆) δ:9.86 (s, 1H), 8.73 (br. s, 1H), 8.11 (d, J=5.5 Hz, 1H), 7.84 (s, 1H),7.79-7.75 (m, 2H), 7.70-7.65 (m, 3H), 7.45-7.37 (m, 2H), 7.26 (d, J=7.4Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.82 (br. s, 1H), 6.42 (d, J=6.9 Hz,1H), 4.00-3.90 (m, 1H), 3.78-3.70 (m, 3), 3.52-3.44 (m, 1H), 3.18 (s,2H), 2.34 (t, J=10.2 Hz, 1H), 1.94-1.81 (m, 2H), 1.65-1.52 (m, 1H), 1.39(s, 9H). LCMS: 723 [M+H].

7c: Preparation ofN-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)-pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)glycinamidehydrochloride

The tert-butyl{2-[(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)-pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)amino]-2-oxoethyl}carbamate(71 mg, 0.098 mmol) was dissolved in dioxane (3 ml) and treated with a4N HCl solution in dioxane (1 ml). The mixture was stirred at roomtemperature for 3 hours. The volatiles were removed in vacuo and theresidue was triturated in ether. Filtration afforded the title compoundas a yellow solid (65 mg). M.p.=208-212° C. 400 MHz ¹H NMR (DMSO-d₆) δ:10.69 (s, 1H), 8.18 (br. s, 3H), 8.13 (d, J=5.9 Hz, 1H), 7.88 (t, J=1.6Hz, 1H), 7.79-7.75 (m, 2H), 7.71-7.66 (m, 3H), 7.48-7.43 (m, 2H), 7.34(d, J=7.8 Hz, 1H), 6.45 (d, J=5.9 Hz, 1H), 5.15 (br. s, 3H), 4.04-3.95(m, 1H), 3.79 (d, J=5.5 Hz, 2H), 3.70 (dd, J=11.3, 4.3 Hz, 1H),3.48-3.41 (m, 1H), 2.57-2.48 (m, 1H), 2.42 (t, J=10.6 Hz, 1H), 1.95-1.82(m, 2H), 1.67-1.54 (m, 1H), 1.48-1.37 (m, 1H). LCMS: 623 [M+H]. Calc.for C₂₈H₂₇N₈O₃S₂Cl 2.52 HCl: C, 47.03; H, 4.16; N, 15.67. found C,47.04; H, 3.97; N, 15.46.

Example 8 Preparation ofN-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)acetamide

The4-[6-(3-aminophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-chlorophenyl)-sulfonyl]piperidin-3-yl}pyrimidin-2-amine(0.1 g, 0.177 mmol) was dissolved in DCM (5 ml) and treated sequentiallywith Hunig's base (46 uL, 0.265 mmol) and acetyl chloride (15 uL, 0.212mmol). The mixture was kept at room temperature for two hours then wasdiluted with DCM (10 ml). The organic phase was washed with water (2×10ml) and with an aqueous sodium chloride solution (10 ml). The organicphase was dried over sodium sulfate and concentrated in vacuo, giving ayellow foam. The product was triturated in ether and filtered off,giving the title compound as a yellow solid (97 mg). M.p.=169-174° C.400 MHz ¹H NMR (DMSO-d₆) δ: 9.89 (s, 1H), 8.72 (br. s, 1H), 8.12 (d,J=5.1 Hz, 1H), 7.82 (s, 1H), 7.80-7.75 (m, 2H), 7.70-7.64 (m, 3H), 7.41(d, J=4.3 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.13(d, J=7.4 Hz, 1H), 6.42 (d, J=5.5 Hz, 1H), 4.00-3.90 (m, 1H), 3.74 (d,J=8.6 Hz, 1H), 3.48 (d, J=11.7 Hz, 1H), 2.54-2.43 (m, 1H), 2.34 (t,J=10.2 Hz, 1H), 2.05 (s, 3H), 1.94-1.81 (m, 2H), 1.65-1.53 (m, 1H),1.44-1.34 (m, 1H). LCMS: 608 [M+H]. Calc. for C₂₈H₂₆N₇O₃S₂Cl 0.38 water0.41 dioxane: C, 54.68; H, 4.65; N, 15.06. found C, 54.68; H, 4.32; N,15.05.

Example 9 Preparation of(2R)-3-[(3R)-3-([4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl]amino)piperidin-1-yl]propane-1,2-diol9a: Preparation ofN-((3R)-1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}piperidin-3-yl)-4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine

The4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]-pyrimidin-2-aminehydrochloride (310 mg, 0.7 mmol) was dissolved in DNF (15 ml) and wastreated successively with Hunig's base (240 uL, 1.4 mmol), potassiumcarbonate (192 mg, 0.7 mmol) and terabutylammonium iodide (26 mg, 0.07mmol). The mixture was heated to 130° C. and the[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methyl-benzenesulfonate(0.2 g, 0.7 mmol) was added in three portions. The mixture was kept at130° C. for 5 hours, at which point no more starting material appears byHPLC. The volatiles were removed in vacuo and the residue was taken upin ether (100 ml). The organic phase was washed with water (2×20 ml) andwith an aqueous sodium chloride solution (20 ml). The organic phase wasdried over sodium sulfate and concentrated in vacuo, giving a yellowoil. The product was purified by flash chromatography (5:4:0.5hexanes/EtOAc, MeOH), affording the title compound as an off-white solid(231 mg, 64%). M.p.=73-75° C. 400 MHz ¹H NMR (DMSO-d₆) δ: 8.71 (br. s,1H), 8.07 (d, J=5.1 Hz, 1H), 7.42 (d, J=4.4 Hz, 1H), 7.36 (t, J=7.9 Hz,1H), 7.19-7.11 (m, 2H), 7.04-6.92 (m, 2H), 6.36 (d, J=5.1 Hz, 1H), 4.19(quintet, J=6.2 Hz, 1H), 3.99 (dd, J=8.1, 6.2 Hz, 1H), 3.96-3.87 (m,1H), 3.77 (s, 3H), 3.52 (t, J=7.5 Hz, 1H), 3.15 (s, 2H), 3.05 (d, J=9.9Hz, 1H), 2.69 (d, J=10.3 Hz, 1H), 2.15 (t, J=9.4 Hz, 1H), 2.04 (t, J=9.5Hz, 1H), 1.90-1.82 (m, 1H), 1.75-1.65 (m, 1H), 1.59-1.48 (m, 1H),1.40-1.25 (m, 1H), 1.29 (s, 3H), 1.21 (s, 3H). LCMS: 521 [M+H].

9b: Preparation of(2R)-3-[(3R)-3-({4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]propane-1,2-diol

TheN-((3R)-1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}piperidin-3-yl)-4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine(150 mg, 0.288 mmol) was dissolved in MeOH (10 ml) and water (1.2 ml)and treated with trifluoroacetic acid (90 uL). The mixture was stirredat 50° C. overnight (18 hours). The mixture was neutralized withpotassium carbonate (160 mg) and the volatiles were removed in vacuo.The product was purified by flash chromatography (6:1 EtOAc/MeOH),affording the title compound as an off-white solid (120 mg, 87%).M.p.=106-108° C. 400 MHz ¹H NMR (DMSO-d₆) δ: 8.72 (br. s, 1H), 8.08 (d,J=5.5 Hz, 1H), 7.44 (d, J=4.4 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.16-7.10(m, 2H), 7.06-6.97 (m, 2H), 6.36 (d, J=5.5 Hz, 1H), 4.40-4.15 (m, 1H),4.02-3.90 (m, 1H), 3.77 (s, 3H), 3.68-3.56 (m, 2H), 3.40-3.28 (m, 2H),3.05-2.95 (m, 1H), 2.80-2.64 (m, 1H), 2.42 (br. s, 1H), 2.32 (br. s,1H), 2.14 (br. s, 1H), 1.90-1.80 (m, 1H), 1.75-1.65 (m, 1H), 1.60-1.45(m, 1H), 1.45-1.30 (m, 1H). LCMS: 481 [M+H].

9c: Preparation of(2R)-3-[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]propane-1,2-diol

The(2R)-3-[(3R)-3-({4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]propane-1,2-diol(150 mg, 0.312 mmol) in methylene chloride (10 ml) was cooled to −78° C.and slowly treated with 1 molar solution of boron tribromide inmethylene chloride (2.5 ml). The reaction mixture was kept at −78° C.for one hour then was allowed to warm to room temperature for 18 hours.The mixture was quenched by the addition of methanol (5 ml) at −78° C.and was stirred at room temperature for an additional hour. The mixturewas concentrated in vacuo and the crude product was purified by flashchromatography (6:1 EtOAc/MeOH+drops of aq. NH₄OH), affording the titlecompound as a pale yellow solid (71 mg, 49%). M.p.=185-187° C. 400 MHz¹H NMR (DMSO-d₆) δ: 9.39 (s, 1H), 8.72 (br. s, 1H), 8.12 (d, J=5.1 Hz,1H), 7.43 (d, J=4.4 Hz, 1H), 7.32 (br. s, 1H), 7.26-7.20 (m, 1H),7.00-6.95 (m, 2H), 6.84-6.81 (m, 1H), 6.45 (d, J=5.5 Hz, 1H), 5.28-5.03(br. s, 1H), 4.90-4.65 (br. s, 1H), 4.34-4.22 (m, 1H), 3.98-3.84 (m,1H), 3.47-3.38 (m, 1H), 3.35-3.25 (m, 1H), 3.15-2.65 (m, 4H), 2.10-1.88(m, 2H), 1.87-1.72 (m, 2H), 1.65-1.40 (m, 2H). LCMS: 467 [M+H].

In addition to those examples of compounds prepared by the methods ofthis invention set forth above, the following non-limiting list ofcompounds prepared by the methods of this invention is set forth inTable I.

Example 10 Preparation of4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-[(3μL-1-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidin-2-amine

To a solution of4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine(200 mg, 0.45 mmol) and Hunig's base (145 μL, 0.90 mmol) in 10 mL DCMwas added a solution of triphosgene (660 mg; 2.25 mmol) in 10 mL DCMdropwise over 10 min with stirring. The mixture was allowed to stir atambient temperature for 1.5 hr. The reaction mixture was thenconcentrated under reduced pressure. The residue was diluted with 20 mLether and concentrated under reduced pressure yielding(3R)-3-({4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carbonylchloride as an off-white solid (190 mg). The solid was diluted in 10 mLDCM. To the resulting solution was added morpholine (60 μL, 0.67 mmol)and triethylamine (70 μL, 0.50 mmol). The mixture was allowed to stir atambient temperature for 20 hr. The reaction mixture was thenconcentrated under reduced pressure and the residue purified by flashchromatography on silica gel (1:4, ethyl acetate:hexanes) to yield4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-[(3R)-1-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidin-2-amineas an off-white solid (50.2 mg, 23%). 400 MHz ¹H NMR (DMSO-d₆) δ: 8.75(s, 1H), 8.20 (s, 1H), 8.11 (d, J=5.2 Hz, 1H), 7.62-7.66 (m, 2H),7.30-7.34 (m, 2H), 6.37 (s, 1H), 3.76 (m, 2H), 3.53 (m, 4H), 3.15 (m,2H), 3.09 (m, 2H), 2.75 (m, 2H), 2.62 (m, 1H), 1.99 (s, 1H), 1.78 (br.s,1H), 1.50-1.54 (m, 2H). LCMS: 492 [M+H].

Example 11 Preparation of5-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}-2-fluorophenol11a Preparation of 2-bromo-1-(4-fluoro-3-methoxy-phenyl)-ethanone

To a mixture of copper (II) bromide (5.31 g, 23.8 mmol) in ethyl acetate(20 ml), heated to 60° C. was added in a dropwise fashion, a solution of3-fluoro-4-methoxyacetophenone (2.0 g, 11.9 mmol) in chloroform (20 ml).The reaction mixture was kept at reflux for 4.5 hours. The mixture wasallowed to cool to room temperature and filtered. The volatiles wereremoved in vacuo, providing a brown oil which was purified by flashchromatography (gradient 5% to 10% ethyl acetate in hexanes). The titlecompound was obtained as an off-white solid (2.4 g, 82%). 400 MHz ¹H NMR(DMSO-d₆) δ 7.72-7.66 (m, 2H), 7.42 (dd, J=11.0, 8.2 Hz, 1H), 4.97 (s,2H), 3.93 (s, 31H). LCMS: 248 [M+H].

11b Preparation of 6-(4-fluoro-3-methoxy-phenyl)-imidazo[2,1-b]thiazole

To a mixture of 2-aminothiazole (0.976 g, 9.74 mmol) and2-bromo-1-(4-fluoro-3-methoxy-phenyl)-ethanone (2.4 g, 9.74 mmol) wasadded absolute ethanol (100 ml). The reaction was allowed to reflux withvigorous stirring for 18 hours (checked by HPLC). The reaction mixturewas reduced to half its original volume in vacuo. The remaining liquidwas poured onto ice and the solution made basic by the addition ofammonium hydroxide solution (30%), until pH is 8. The mixture wasextracted with ethyl acetate (2×100 ml). The combined extracts werewashed with water (100 ml) and saturated aqueous sodium chloridesolution (100 ml). The organic phase was dried with sodium sulfate,filtered and concentrated in vacuo, to give an orange solid.Purification by flash chromatography (gradient 25%-50% ethyl actetate inhexanes) afforded the title product as a pale yellow solid (1.59 g,66%). 400 MHz ¹H NMR (DMSO-d₆) δ 8.26 (s, 1H), 7.95 (d, J=2.3 Hz, 1H),7.61 (dd, J=8.6, 2.0 Hz, 1H), 7.39 (ddd, J=8.2, 4.3, 2.0 Hz, 1H); 7.28(d, J=4.7 Hz, 1H), 7.22 (dd, J=11.3, 8.2 Hz, 1H), 3.91 (s, 3H). LCMS:249 [M+H].

11c: Preparation of1-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone

To a mixture of 6-(4-fluoro-3-methoxyphenyl)-imidazo[2,1-b]thiazole (1.0g, 4.03 mmol) and acetic anhydride (25 ml), heated to 140° C., was added43 μl of concentrated sulfuric acid. The reaction mixture was heated at140° C. for 1 hour. The reaction was monitored by HPLC. After one hour,only 10% product was observed. Another 43 μl of concentrated sulfuricacid was added and the mixture was kept at 140° C. for 4 hours. Thereaction mixture was then poured onto 50 ml of ice, and diluted with 50ml of water and the resulting mixture was extracted two times with 100ml each of ethyl acetate. The combined extracts were washed with twoportions of 50 ml of water and two portions of 50 ml of saturatedaqueous sodium chloride solution. The organic phase was dried withsodium sulfate, filtered and concentrated in vacuo, to give a brownsolid. The product,-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone,was purified by flash chromatography (gradient 25%-50% ethyl acetate inhexanes) and obtained as a pale yellow solid (1.12 g, 96%). 400 MHz ¹HNMR (DMSO-d₆) δ 8.44 (d, J=4.3 Hz, 1H), 7.56 (d, J=4.3 Hz, 1H), 7.43(dd, J=8.2, 2.0 Hz, 1H), 7.34 (dd, J=11.7, 8.6 Hz, 1H), 7.21 (ddd,J=8.2, 4.3, 2.0 Hz, 1H), 3.89 (s, 3H), 2.14 (s, 3H). LCMS: 291 [M+H].

11d: Preparation of3-(dimethylamino)-1-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]prop-2-en-1-one

A 100 ml round bottom flask was charged with the1-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone(1.12 g, 3.86 mmol) and dimethylformamide dimethylacetal (25 ml). Themixture was refluxed for 20 hours and then cooled to room temperature.The mixture was concentrated in vacuo and the residue was purified byflash chromatography (ethyl acetate), giving a pale yellow solid (1.138g, 85%). 400 MHz ¹H NMR (DMSO-d₆) δ: 8.39 (d, J=4.7 Hz, 1H), 7.62 (d,J=12.5 Hz, 1H), 7.45-7.40 (m, 2H), 7.31 (dd, J 11.3, 8.2 Hz, 1H), 7.20(ddd, J=8.2, 4.3, 2.0 Hz, 1H), 5.10 (d, J=12.5 Hz, 1H), 3.87 (s, 3H),3.06 (br. s, 3H), 2.49 (br. s, 3H). LCMS: 346 [M+H].

11e: Preparation of tert-butyl(3R)-3-({4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate

A mixture of3-(dimethylamino)-1-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]triazol-5-yl]prop-2-en-1-one(0.6 g, 1.74 mmol) and tert-butyl(3R)-3-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylatehydrochloride (0.726 g, 2.61 mmol) was diluted with 13 ml of absoluteethanol and treated with 1.35 eq. of a 21% w/w solution of sodiumethoxide in ethanol (875 μl) to form a reaction mixture. The reactionmixture was heated to reflux for 24 hours. HPLC revealed remainingstarting enaminone. More tert-butyl(3R)-3-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylatehydrochloride (0.243 g, 0.87 mmol) was added followed by a 21% w/wsolution of sodium ethoxide in ethanol (270 μl). The mixture was kept atreflux for an additional 15 hours. Volatiles were removed in vacuo andthe residue was taken up in 50 ml of ethyl acetate and 50 ml of water.The phases were separated and the aqueous phase was extracted with 50 mlof ethyl acetate. The combined organic extracts were washed with 100 mlof water, and then with a saturated sodium chloride solution (100 ml).The organic phase was dried with sodium sulfate, filtered andconcentrated in vacuo, to give a brown oil. The product was purified byflash chromatography on silica gel (gradient 50% to 75% ethyl acetate inhexanes) to yield 0.785 g of a pale yellow solid (86%). 400 MHz ¹H NMR(DMSO-d₆ at 60° C.) δ: 8.72 (br. s, 1H), 8.13 (d, J=5.5 Hz, 1H), 7.41(d, J=4.7 Hz, 1H), 7.35 (dd, J=8.6, 2.0 Hz, 1H), 7.26 (dd, J=11.7, 8.6Hz, 1H), 7.18-7.08 (m, 2H), 6.41 (d, J=5.5 Hz, 1H), 4.00-3.90 (m, 1H),3.84 (s, 3H), 3.85-3.75 (m, 1H), 3.72-3.63 (m, 1H), 3.00-2.88 (m, 2H),2.04-1.94 (m, 1H), 1.82-1.73 (m, 1H), 1.62-1.50 (m, 1H), 1.50-1.38 (m,1H), 1.34 (s, 9H). LCMS: 525 [M+H].

11f: Preparation of4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-aminehydrochloride

The tert-butyl(3R)-3-({4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate(0.785 g, 1.50 mmol) was dissolved in 15 ml of dioxane and treated with7.5 ml of anhydrous 4N HCl in dioxane at room temperature. The reactionmixture was stirred at room temperature for two hours. The mixture wasthen diluted with 25 ml of ether and stirred until product separated asa solid. Solid product was filtered and washed with ether. The solid wasdissolved in MeOH (20 ml) and concentrated to dryness twice. The productwas dried at high vacuum to yield 0.709 g of yellow solid (bis HCl salt)(95%). 400 MHz ¹H NMR (DMSO-d₆ at 60° C.) δ: 11.65 (br. s, 2H), 9.60(br. s, 1H), 8.90 (br. s, 1H), 8.14 (d, J=6.3 Hz, 1H), 7.61 (m, 1H),7.40 (dd, J=8.6, 2.0 Hz, 1H), 7.33 (dd, J=11.7, 8.6 Hz, 1H), 7.20 (ddd,J=8.2, 4.3, 2.0 Hz, 1H), 6.55 (d, J=6.3 Hz, 1H), 4.50-4.40 (m, 1H), 3.86(s, 3H), 3.48-3.38 (m, 1H), 3.22-3.10 (m, 1H), 3.06-2.88 (m, 2H),2.12-2.02 (m, 1), 2.00-1.84 (m, 2H), 1.78-1.64 (m, 1H). LCMS: 425 [M+H].

11g: Preparation ofN-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine

The4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-aminehydrochloride (0.25 g, 0.50 mmol) in methylene chloride (DCM) (12 ml)was cooled to 0° C. and was treated with Hunig's base (440 μl, 2.5mmol). The mixture was kept at 0° C. for 30 minutes then the4-chlorophenylsulfonyl chloride (0.128 g, 0.60 mmol) was added. Thereaction mixture was stirred at room temperature for one hour. Themixture was diluted with methylene chloride (10 ml) and was washed water(2×10 ml) and a saturated aqueous sodium chloride solution (10 ml). Theorganic phase was dried over sodium sulfate and concentrated in vacuo.The crude product was purified by flash chromatography using a gradient(ethyl acetate/hexanes, 50-75%), affording 0.281 g (94%) of the titlecompound as a pale yellow solid. M.p.: 142-143° C. 400 MHz ¹H NMR(DMSO-d₆ at 60° C.) δ: 8.71 (br. s, 1H), 8.15 (d, J=5.5 Hz, 1H),7.80-7.74 (m, 2H), 7.70-7.64 (m, 2H), 7.42 (d, J=4.5 Hz, 1H), 7.36 (dd,J=8.6, 2.3 Hz, 1H), 7.27 (dd, J=11.3, 8.2 Hz, 1H), 7.19-7.12 (m, 2H),6.43 (d, J=5.5 Hz, 1H), 4.00-3.90 (m, 1H), 3.84 (s, 3H), 3.77-3.70 (m,1H), 3.52-3.44 (m, 1H), 2.56-2.42 (m, 1H), 2.34 (t, J=10.0 Hz, 1H),1.95-1.80 (m, 2H), 1.66-1.52 (m, 1H), 1.45-1.33 (m, 1H). LCMS: 599[M+H]. Calc. for C₂₇H₂₄N₆O₃S₂FCl 0.16 water 0.74 diethyl ether: C,53.94; H, 4.57; N, 12.60. found C, 53.94; H, 4.19; N, 12.59.

11h: Preparation of3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}-2-fluorophenol

TheN-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(4-fluoro-3-methoxy-phenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine(0.251 g, 0.42 mmol) in methylene chloride (8 ml) was cooled to −78° C.and slowly treated with 1 molar solution of boron tribromide inmethylene chloride (3.4 ml). The reaction mixture was kept at −78° C.for one hour then was allowed to warm to room temperature for two hours.The mixture was quenched by the addition of methanol (900 μl) at −78° C.and was stirred at room temperature for an additional hour. The mixturewas diluted with methylene chloride (100 ml) and washed with threeportions of 25 ml of saturated sodium bicarbonate solution, two portionsof 25 ml of water and two portions of 25 ml of saturated sodium chloridesolution. The organic phase was dried over sodium sulfate andconcentrated in vacuo, giving a yellow solid. The crude product waspurified by flash chromatography using a gradient (ethylacetate/hexanes, 50-75%), affording 0.063 g of the title compound as apale yellow solid. M.p.=172-175° C. 400 MHz ¹H NMR (DMSO-d₆ at 60° C.)δ: 9.84 (s, 1H), 8.70 (br. s, 1H), 8.15 (d, J=5.5 Hz, 1H), 7.80-7.74 (m,2H), 7.70-7.64 (m, 2H), 7.40 (d, J=4.3 Hz, 1H), 7.19 (dd, J=13.3, 8.6Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.13 (br. d, J=7.8 Hz, 1H), 6.99 (ddd,J=8.2, 4.3, 2.0 Hz, 1H), 6.42 (d, J=5.1 Hz, 1H), 4.00-3.90 (m, 1H),3.76-3.69 (m, 1H), 3.51-3.43 (m, 1H), 2.58-2.42 (m, 1H), 2.35 (t, J=10.6Hz, 1H), 1.94-1.80 (m, 2H), 1.66-1.50 (m, 1H), 1.45-1.32 (m, 1H). LCMS:585 [M+H]. Calc. for C₂₆H₂₂N₆O₃S₂FCl 0.89 diethyl ether: C, 53.51; H,4.42; N, 12.67. found C, 53.76; H, 4.22; N, 12.66.

Example 12 Preparation of5-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]-2-fluorophenol12a: Preparation of tert-butyl4-{(4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate

A mixture of3-(dimethylamino)-1-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]prop-2-en-1-one(0.537 g, 1.55 mmol) and tert-butyl4-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylate hydrochloride(0.650 g, 2.33 mmol) was diluted with 13 ml of absolute ethanol andtreated with 1.35 eq. of a 21% w/w solution of sodium ethoxide inethanol (780 μl) to form a reaction mixture. The reaction mixture washeated to reflux for 24 hours. Volatiles were removed in vacuo and theresidue was taken up in 50 ml of ethyl acetate and 50 ml of water. Thephases were separated and the aqueous phase was extracted with 50 ml ofethyl acetate. The combined organic extracts were washed with 100 ml ofwater, and then with a saturated sodium chloride solution (100 ml). Theorganic phase was dried with sodium sulfate, filtered and concentratedin vacuo, to give a brown oil. The product was purified by flashchromatography on silica gel (gradient 50% to 75% ethyl acetate inhexanes) to yield 0.713 g of a pale yellow solid (88%). 400 MHz ¹H NMR(DMSO-d₆ at 60° C.) δ: 8.71 (br. s, 1H), 8.11 (d, J=5.5 Hz, 1H), 7.45(d, J=4.3 Hz, 1H), 7.35 (dd, J=8.2, 2.0 Hz, 1H), 7.26 (dd, J=11.3, 8.2Hz, 1H), 7.19-7.12 (m, 2H), 6.39 (d, J=5.1 Hz, 1H), 3.98-3.87 (m, 3H),3.83 (s, 3H), 2.91 (t, J=11.5 Hz, 2H), 1.94-1.87 (m, 2H), 1.47-1.35 (m,2H), 1.42 (s, 9H). LCMS: 525 [M+H].

12b: Preparation of4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[piperidin-4-yl]pyrimidin-2-aminehydrochloride

The tert-butyl4-({4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate(0.713 g, 1.36 mmol) was dissolved in 15 ml of dioxane and treated with7.5 ml of anhydrous 4N HCl in dioxane at room temperature (RT). Thereaction mixture was stirred at room temperature for two hours. Themixture was then diluted with 25 ml of ether and stirred until productseparated as a solid. Solid product was filtered and washed with ether.The solid was dissolved in MeOH (20 ml) and concentrated to drynesstwice. The product was dried at high vacuum to yield 0.652 g of yellowsolid (bis HCl salt) (96%). 400 MHz ¹H NMR (DMSO-d₆ at 60° C.) δ: 9.32(br. s, 1H), 8.10 (d, J=4.7 Hz, 1H), 7.61 (d, J=4.3 Hz, 1H), 7.39 (dd,J=8.2, 2.0 Hz, 1H), 7.33 (dd, J=11.3, 8.2 Hz, 1H), 7.19 (ddd, J=8.2,4.3, 2.0 Hz, 1H), 6.56 (d, J=6.7 Hz, 1H), 4.30-4.20 (m, 1H), 3.86 (s,3H), 3.40-3.32 (m, 2H), 3.12-2.96 (m, 2H), 2.22-2.12 (m, 2H), 1.99-1.86(m, 2H). LCMS: 425 [M+H].

12c: Preparation ofN-[1-(cyclopropylsulfonyl)piperidin-4-yl]-4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine

The4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[piperidin-4-yl]pyrimidin-2-aminehydrochloride (0.25 g, 0.50 mmol) in methylene chloride (DCM) (12 ml)was cooled to 0° C. and was treated with Hunig's base (440 μl, 2.5mmol). The mixture was kept at 0° C. for 30 minutes then thecyclopropyl-sulfonyl chloride (72 μl, 0.60 mmol) was added. The reactionmixture was stirred at room temperature for one hour. The mixture wasdiluted with methylene chloride (10 ml) and was washed water (2×10 ml)and a saturated aqueous sodium chloride solution (10 ml). The organicphase was dried over sodium sulfate and concentrated in vacuo. The crudeproduct was purified by flash chromatography using a gradient (ethylacetate/hexanes, 30-75%), affording 0.253 g (96%) of the title compoundas a pale yellow solid. M.p.: 146-148° C.400 MHz ¹H NMR (DMSO-d₆ at 60°C.) δ: 8.72 (br. s, 1H), 8.13 (d, J=5.1 Hz, 1H), 7.45 (d, J=4.3 Hz, 1H),7.35 (dd, J=8.6, 2.0 Hz, 1H), 7.26 (dd, J=11.3, 8.2 Hz, 1H), 7.25 (br.S, 1H), 7.15 (ddd, J=8.2, 4.7, 2.0 Hz, 1H), 6.41 (d, J=5.1 Hz, 1H),3.95-3.86 (m, 1H), 3.83 (s, 3H), 3.68-3.61 (m, 2H), 3.06-2.96 (m, 2H),2.60-2.52 (m, 1H), 2.08-1.96 (m, 2H), 1.66-1.54 (m, 2H), 1.04-0.94 (m,4H). LCMS: 529 [M+H]. Calc. for C₂₄H₂₅N₆O₃S₂F 0.13 water 0.7 diethylether: C, 54.31; H, 5.25; N, 14.18. found C, 54.32; H, 4.89; N, 14.19.

12d: Preparation of5-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]-2-fluorophenol

TheN-[1-(cyclopropylsulfonyl)piperidin-4-yl]-4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine(0.226 g, 0.43 mmol) in methylene chloride (8 ml) was cooled to −78° C.and slowly treated with 1 molar solution of boron tribromide inmethylene chloride (3.4 ml). The reaction mixture was kept at −78° C.for one hour then was allowed to warm to room temperature for two hours.The mixture was quenched by the addition of methanol (900 μl) at −78° C.and was stirred at room temperature for an additional hour. The mixturewas diluted with methylene chloride (100 ml) and washed with threeportions of 25 ml of saturated sodium bicarbonate solution, two portionsof 25 ml of water and two portions of 25 ml of saturated sodium chloridesolution. The organic phase was dried over sodium sulfate andconcentrated in vacuo, giving a yellow solid. The crude product waspurified by flash chromatography (ethyl acetate), affording 0.19 g (86%)of the title compound as a beige solid. M.p.=224-225° C. 400 MHz ¹H NMR(DMSO-d₆ at 60° C.) δ: 9.82 (s, 1H), 8.67 (br. s, 1H), 8.12 (d, J=5.5Hz, 1H), 7.43 (d, J=4.3 Hz, 1H), 7.25-7.14 (m, 3H), 6.99 (ddd, J=8.2,4.3, 2.0 Hz, 1H), 6.41 (d, J=5.1 Hz, 1H), 3.95-3.84 (m, 1H), 3.68-3.60(m, 2H), 3.00 (td, J=11.9, 2.7 Hz, 2H), 2.59-2.52 (m, 1H), 2.06-1.98 (m,2H), 1.66-1.54 (m, 2H), 1.04-0.92 (m, 4H). LCMS: 515 [M+H]. Calc. forC₂₃H₂₃N₆O₃S₂F 0.53 diethyl ether 0.17 water: C, 53.46; H, 4.93; N,14.89. found C, 53.46; H, 4.60; N, 14.88.

Example 13 Preparation ofN-[(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl]-4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine13a: Preparation of 6-(3-cyanophenyl)-imidazo[2,1-b]thiazole

To a mixture of 2-aminothiazole (3.29 g, 32.9 mmol) and2-bromo-3′-cyano-acetophenone (7.37 g, 32.9 mmol) was added absoluteethanol (250 mL). The reaction was allowed to reflux with vigorousstirring for 20 hours. The reaction mixture was reduced to half itsoriginal volume in vacuo. The remaining suspension was poured ontoice-water (200 mL) and the resulting mixture was basified by addition ofammonium hydroxide solution (30%, 100 mL). Product was collected byfiltration and washed with water (50 mL), dried in a vacuum oven at 50°C. to provide 6-(3-cyanophenyl)-imidazo[2,1-b]thiazole (6.0 g, 81%). Itwas used with out further purification. LCMS: 226 [M+H].

13b: Preparation of1-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone

To a mixture of 6-(3-cyanophenyl)-imidazo[2,1-b]thiazole (5.50 g, 24.4mmol) and acetic anhydride (50 mL) was added 0.6 mL of concentratedsulfuric acid. The reaction mixture was heated at 135° C. for 5 hours.After cooling to room temperature, the reaction mixture was diluted withdichloromethane (100 mL), washed with water (50 mL×2), saturated aqueoussodium bicarbonate solution (50 mL×2), water (50 mL), dried over sodiumsulfate, filtered and concentrated in vacuo. Product was purified byflash chromatography on silica gel eluting with 40% ethyl acetate inhexane to yield 4.8 g (74%) of the title compound as a light yellowsolid. LCMS: 268 [M+H].

13c: Preparation of3-(dimethylamino)-1-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]prop-2-en-1-one

A 100 mL round bottom flask was charged with the1-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone (4.30 g,16.1 mmol) and dimethylformamide dimethylacetal (40 mL). The mixture wasrefluxed for 6 hours and then concentrated in vacuo to provide a darksolid. LCMS: 323 [M+H]; purity: 90% by UV at 254 nm. This crude was usedfor next step reaction without further purification.

13d: Preparation of tert-butyl(3R)-3-({4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate

To a mixture of3-(dimethylamino)-1-[6-(3-cyanoyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]prop-2-en-1-one(˜16 mmol, crude) and tert-butyl(3R)-3-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylatehydrochloride (6.71 g, 24.15 mmol) in 20 mL of absolute ethanol wasadded a solution of sodium ethoxide in ethanol (21% w/w, 6.8 mL). Themixture was heated to reflux for 24 hours. Then 3.0 mL of sodiumethoxide in ethanol (21% w/w) was added and the mixture was stirred forfurther 18 hours. Volatiles were removed in vacuo and the residue wastaken up in 200 mL of dichloridementhane, washed with water (100 mL×2),dried over sodium sulfate and concentrated. The product was purified byflash chromatography on silica gel (ethyl acetate/hexanes, 50%) to yield4.7 g of a pale yellow solid (59%). M.p.=108-110° C.; 400 MHz ¹H NMR(DMSO-d₆ at 60° C.) δ: 8.65 (bs, 1H), 8.15 (d, J=5.2 Hz, 1H), 8.00-7.99(m, 1H), 7.93-7.90 (m, 1H), 7.86-7.83 (m, 1H), 7.64 (t, J=7.6 Hz, 1H),7.43 (d, J=4.4 Hz, 1H), 7.16 (d, J=6.8 Hz, 1H), 6.34 (d, J=4.8 Hz, 1H),3.93 (bs, 1H), 3.80-3.73 (m, 1H), 3.73 (bs, 1H), 2.92 (bs, 2H),1.98-1.94 (m, 1H), 1.77-1.74 (m, 1H), 1.59-1.51 (m, 1H), 1.47-1.31 (m,1H), 1.31 (s, 9H). LCMS: 502 [M+H].

13e: Preparation of4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-aminehydrochloride

The tert-butyl(3R)-3-({4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate(2.90 g, 5.79 mmol) was dissolved in 20 mL of ethyl acetate and treatedwith 30 mL of 3.0 M HCl in ethyl acetate at room temperature (RT)overnight. Solid product was filtered, washed with ethyl acetate anddried under vacuum overnight to provide the title compound as a yellowsolid. It was used without further purification. LCMS: 402 [M+H].

13e: Preparation ofN-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine

The4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-aminehydrochloride (˜5.79 mmol) in dichloromethane (DCM) (50 mL) was cooledto 0° C. and treated with triethylamine (4.0 mL, 28.9 mmol), then4-chlorophenylsulfonyl chloride (1.34 g, 6.37 mmol) was added. Thereaction mixture was stirred at room temperature for 1 hour, dilutedwith dichloromethane (100 mL), washed with water (50 mL×3), dried oversodium sulfate and concentrated in vacuo to provide 3.22 g (97%) of thetitle compound as a yellow solid. M.p.=144-146° C.; 400 MHz ¹H NMR(DMSO-d₆ at 60° C.) δ: 8.65 (br. s, 1H), 8.17 (d, J=5.2 Hz, 1H), 8.01(s, 1H), 7.94 (dd, J=0.8 and 7.6 Hz, 1H), 7.82-7.85 (m, 1H), 7.77-7.75(m, 2H), 7.67-7.64 (m, 3H), 7.44 (d, J=4.4 Hz, 1H), 7.18 (d, J=7.2 Hz,1H), 6.37 (d, J=4.8 Hz, 1H), 3.91 (bs, 1H), 3.72 (d, J=10.8 Hz, 1H),3.48 (d, J=10.8 Hz, 1H), 2.48-2.45 (m, 1H), 2.32 (t, J=10 Hz, 1H),1.89-1.82 (m, 2H), 1.60-1.56 (m, 1H), 1.41-1.36 (m, 1H). LCMS: 576[M+H].

Example 14 Preparation of3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}-N′-hydroxybenzenecarboximidamide

To a suspension ofN-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-cyano-phenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine(0.050 g, 0.086 mmol) in 80% ethanol-water (2.5 mL) was added an aqueoussolution (0.50 mL) containing 6.65 mg of hydroxylamine hydrochloride(1.1 equivalents) and 4.61 mg of sodium carbonate (0.5 equivalents). Theresulting solution was heated at 80° C. for 20 hours. Solid wascollected by filtration and treated with hot (80° C.) 80% ethanol-water(2 mL×5). Solid was collected and dried under vacuum at 45° C. overnightto afford 25 mg (48%) of the title compound as a yellow solid.M.p.=272-273° C. 400 MHz ¹H NMR (DMSO-d₆ at 60° C.) δ: 9.52 (s, 1H),8.70 (bs, 1H), 8.11 (d, J=5.2 Hz, 1H), 7.93 (s, 1H), 7.77-7.73 (m, 3H),7.67-7.66 (m, 2H), 7.59 (d, J=6.8 Hz, 1H), 7.47-7.40 (m, 2H), 7.11 (d,J=7.6 Hz, 1H), 6.38 (d, J=4.4 Hz, 1H), 5.68 (s, 2H), 3.94 (br. s, 1H),3.73 (d, J=8.4 Hz, 1H), 3.48 (d, J=10.8 Hz, 1H), 2.49-2.48 (m, 1H), 2.35(t, J=8.8 Hz, 1H), 1.95-1.84 (m, 21), 1.60-1.5 (m, 1H), 1.46-1.30 (m,1H). LCMS: 610 [M+H].

Example 15 Preparation of3-(5-{2-[(R)-1-(4-chloro-benzenesulfonyl)-piperidin-3-ylamino]-pyrimidin-4-yl}-imidazo[2,1-b]thiazol-6-yl)-benzamide

To a solution ofN-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-cyano-phenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine(0.50 g, 0.87 mmol) in dichloromethane (DCM) (10 mL) at −78° C. wasadded a solution of borane tribromide (BBr₃) (1.74 mL, 1.0 M in DCM).The mixture was stirred at −78° C. for 0.5 hour, then room temperaturefor one hour. The mixture was then cooled to −78° C. and methanol (1 mL)was added. The resulting mixture was stirred at room temperatureovernight. Solvent was removed in vaco, the residue was treated with a1:1 mixture of dichloromethane and water (50 mL). Organic layer wasseparated, dried over sodium sulfate and concentrated. Product waspurified by flash chromatography on silica gel eluting with 5% methanolin dichloromethane to afford 0.019 g (4%) of the title compound as ayellow solid. M.p.=168-170° C. 400 MHz ¹H NMR (DMSO-d₆ at 60° C.) δ:8.70 (br. s, 1H), 8.10 (s, 1H), 8.10 (d, J=4.8 Hz, 1H), 7.94 (d, J=7.6Hz, 1H), 7.94-7.80 (m, 1H), 7.77-7.65 (m, 4H), 7.53 (t, J=8.0 Hz, 1H),7.42 (d, J=4.4 Hz, 1H), 7.25-7.13 (m, 2H), 7.15 (d, J=7.2 Hz, 1H), 6.34(d, J=5.6 Hz, 1H), 3.92 (bs, 1H), 3.73 (d, J=8.4 Hz, 1H), 3.48 (d,J=11.2 Hz, 1H), 2.48-2.43 (m, 1H), 2.35 (t, J=10.8 Hz, 1H), 1.90-1.82(m, 2M), 1.59-1.56 (m, 1H), 1.39-1.34 (m, 1H). LCMS: 595 [M+H].

Example 16 Preparation of3-(5-{2-[(3R)-piperidin-3-ylamino]pyrimidin-4-yl}imidazo[2,1-b][1,3]thiazol-6-yl)benzamide16a: Preparation of(R)-3-{4-[6-(3-carbamoyl-phenyl)-imidazo[2,1-b]thiazol-5-yl]-pyrimidin-2-ylamino}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of tert-butyl(3R)-3-({4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate(0.204 g, 0.407 μmmol) in ethanol (5 mL) was added 25% aqueous sodiumhydroxide (0.072 mL, 0.448 mmol). The mixture was heated at 75° C. for20 hours. Solvent was removed to dryness. Residue was taken intodichloromethane (20 mL), washed with water (5 mL), dried over sodiumsulfate and concentrated. Product was purified by flash chromatographyon silica gel eluting with 5% methanol in dichloromethane to afford0.175 g (83%) of the title compound as an off-white solid. M.p.=161-165°C. 400 MHz ¹H NMR (DMSO-d₆ at 60° C.) δ: 8.70 (br. s, 1H), 8.14 (s,114), 8.10 (d, J=5.6 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.72 (d, J=7.6 Hz,1H). 7.54 (t, J=7.6 Hz, 1H), 7.44 (d, J=4.4 Hz, 1H), 7.30-7.14 (bs, 2H),7.15 (d, J=6.8 Hz, 1H), 6.33 (d, J=5.2 Hz, 1H), 3.96 (bs, 1H), 3.81-3.77(m, 1H), 3.68 (bs, 1H), 2.94-2.90 (m, 2H), 2.00-1.97 (m, 1H), 1.80-1.77(m, 1H), 1.59-1.53 (m, 1H), 1.46-1.40 (m, 1H), 1.34 (s, 9H); LCMS: 520[M+H].

16b: Preparation of345-{2-[(3R)-piperidin-3-ylamino]pyrimidin-4-yl}imidazo[2,1-b][1,3]thiazol-6-yl)benzamide

(R)-3-{4-[6-(3-carbamoyl-phenyl)-imidazo[2,1-b]thiazol-5-yl]-pyrimidin-2-ylamino}-piperidine-1-carboxylicacid tert-butyl ester (0.15 g, 0.289 mmol) was dissolved in 3 mL ofethyl acetate and treated with 3 ml of 3.0 M HCl in ethyl acetate atroom temperature (RT) evernight. Solid product was filtered, washedethyl acetate and dried under vacuum overnight to provide 0.130 g (97%)of the title compound as a yellow solid. M.p.=202-205° C. 400 MHz ¹H NMR(DMSO-d₆ at 60° C.) δ: 9.35 (br. s, 1H), 9.20-8.25 (bs, 3H), 8.12-8.09(m, 2H), 7.98-7.968.0 (m, 1H), 7.74-7.72 (m, 1H), 7.57-7.52 (m, 2H),7.25 (bs, 1H), 6.40 (d, J=6.0 Hz, 1H), 4.31 (br. s, 1H), 3.40 (d, J=9.2Hz, 1H), 3.16-3.13 (m, 1H), 2.94-2.90 (m, 2H), 2.03-1.97 (m, 1H),1.96-1.89 (m, 1H), 1.89-1.80 (bs, 1H), 1.66-1.60 (m, 1H); LCMS: 459[M+H]. calc. for C₂₁H₂₁N₇OS 3.14 (HCl), 0.25 (EtOAc) C, 47.52; H, 4.74;N, 17.63. found C, 47.57; H, 4.44; N, 17.52; LCMS: 420 [M+H].

Example 17 Preparation of3-{5-[2-([(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl]amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzoicAcid 17a: Preparation of3-(5-{2-[(R)-1-(4-Chloro-benzenesulfonyl)-piperidin-3-ylamino]-pyrimidin-4-yl}-imidazo[2,1-b]thiazol-6-yl)-N-methoxy-N-methyl-benzamide

To a solution ofN-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-cyano-phenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine(1.43 g, 2.49 mmol) in ethanol (30 mL) was added 25% aqueous sodiumhydroxide (1.5 mL, 15.5 mmol). The mixture was heated at 75° C. for 5days. Solvent was removed to dryness. Residue was dissolved into amixture of dichloromethane (100 mL) and 0.5 N HCl (40 mL). Organic layerwas separated, dried over sodium sulfate and concentrated to dryness.The residue was dried further under high vacuum for 24 hours. It wasused without further purification.

The crude product was dissolved in N,N-dimethylformamide (30 mL). To theresulting solution was addedO-benzotriazole-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) (1.42 g, 3.74 mmol), triethylamine (1.04 mL, 7.47 mmol), lastly,a solution of N,O-dimethyl hydroxylamine hydrochloride (0.365 S, 3.74mmol). The mixture was stirred at room temperature for 1 hour, dilutedwith dichloromethane (100 mL), washed with water (50 mL×4), dried oversodium sulfate and concentrated. Product was purified by flashchromatography on silica gel(methanol:dichloromethane:ethylacetate=0.5:7:2) to afford the titlecompound 0.976 g (62%, two steps) as a pale yellow solid. M.p.=114-115°C. 400 MHz ¹H NMR (DMSO-d₆ at 60° C.) δ: 8.70 (br. s, 1H), 8.11 (d,J=4.6 Hz, 1H), 7.77-7.74 (m, 3H), 7.71 (d, J=8.0 Hz, 1H), 7.68-7.62 (m,3H), 7.53 (t, J=7.2 Hz, 1H), 7.41 (d, J=4.4 Hz, 1H), 7.14 (d, J=6.8 Hz,1H), 6.40 (d, J=5.8 Hz, 1H), 3.93 (br. s, 1H), 3.73-3.71 (m, 1H), 3.54(s, 3H), 3.48-3.45 (m, 10H), 3.25 (s, 3H), 2.48-2.43 (m, 1H), 2.33 (t,J=10.0 Hz, 1H), 1.89-1.82 (m, 2H), 1.59-1.56 (m, 1H), 1.41-1.32 (m,1H).LCMS: 639 [M+H].

17b: Preparation of3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzoicAcid

To a solution of3-(5-{2-[(R)-1-(4-chloro-benzenesulfonyl)-piperidin-3-ylamino]-pyrimidin-4-yl}-imidazo[2,1-b]thiazol-6-yl)-N-methoxy-N-methyl-benzamide(0.57 g, 0.089 mmol) in a mixture of methanol (1.0 mL) andtetrahydrofuran (THF) (3.0 mL) was added a solution of lithium hydroxide(0.075 g, 0.179 mmol.) in water (1.0 mL). The mixture was stirred atroom temperature for 48 hours. Solvent was removed to dryness. Residuewas dissolved into a mixture of dichloromethane (20 mL) and 1.0 N HCl(1.0 mL). Organic layer was separated, washed with water (5 mL×4), driedover sodium sulfate and concentrated to dryness. The residue was driedfurther under high vacuum at 45° C. for 24 hours to provide 0.45 g (85%)as a yellow solid. M.p.=190-195° C. 400 MHz ¹H NMR (DMSO-d₆ at 60° C.)δ: 8.70 (br. s, 1H), 8.16 (bs, 1H), 8.12 (d, J=5.2 Hz, 1H), 7.99 (d,J=8.0 Hz, 1H), 7.78-7.83 (m, 1H), 7.77-7.74 (m, 2H), 7.68-7.65 (m, 2H),7.58 (t, J=8.0 Hz, 1H), 7.41 (d, J=4.4 Hz, 1H), 7.17 (d, J=6.8 Hz, 1H),6.37 (d, J=5.2 Hz, 1H), 3.92 (br. s, 1H), 3.75-3.71 (m, 1H), 3.48-3.45(m, 1H), 2.49-2.43 (m, 1H), 2.32 (t, J=10.4 Hz, 1H), 1.90-1.82 (m, 2H),1.59-1.56 (m, 1H), 1.39-1.32 (m, 1H).LCMS: 596 [M+H].

Example 18 Preparation of(1E)-1-(3-[5-[2-([(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl]amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl]phenyl)ethanoneoxime 18a: Preparation of1-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanone

To a solution of3-(5-{2-[(R)-1-(4-chloro-benzenesulfonyl)-piperidin-3-ylamino]-pyrimidin-4-yl}-imidazo[2,1-b]thiazol-6-yl)-N-methoxy-N-methyl-benzamide(0.10 g, 0.157 mmol) in anhydrous tetrahydrofuran (THF) (3.0 mL) at 0°C. was added a solution of methyl magnesium chloride (3.0 M in THF)(0.523 mL, 1.57 mmoL). The mixture was stirred for 3 hours, thenquenched with saturated aqueous ammonium chloride solution (1 mL).Product was extracted with 10 mL of dichloromethane, washed with water(5 mL×2), dried over sodium sulfate and concentrated. Product waspurified by flash chromatography on silica gel (40% dichloromethane inethyl acetate) to afford 0.085 g (91%) of the title compound as a paleyellow solid. M.p.=124-127° C. 400 MHz ¹H NMR (DMSO-d₆ at 60° C.) δ:8.70 (br. s, 1H), 8.17 (m, 1H), 8.12 (d, J=5.6 Hz, 1H), 7.9 (d, J=7.6Hz, 1H), 7.86-7.84 (m, 1H), 7.77-7.74 (m, 2H), 7.67-7.65 (m, 2H), 7.62(t, J=8.0 Hz, 1H), 7.42 (d, J=4.8 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.38(d, J=5.2 Hz, 1H), 3.93 (bs, 1H), 3.74-3.72 (m, 1H), 3.48-3.45 (m, 1H),2.57 (s, 3H), 2.49-2.45 (m, 1H), 2.32 (t, J=10.4 Hz, 1H), 1.90-1.82 (m,2H), 1.59-1.56 (m, 1H), 1.39-1.32 (m, 1H); LCMS: 594 [M+H].

18b: Preparation of(1E)-1-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanoneoxime

To a mixture of1-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanone(0.10 g, 0.168 mmol) and hydroxylamine hydrochloride (0.0125 g, 0.188mmol.) in methanol (2.0 mL) was added 0.2 mL of acetic acid. The mixturewas heated at 50° C. for 3 hours. After cooled to room temperature, themixture was diluted with dichloromethane (10 mL), washed with saturatedaqueous sodium bicarbonate (5 mL×3), water (5 mL), dried over sodiumsulfate and concentrated. Product was purified by flash chromatographyon silica gel (methanol:dichloromethane:ethylacetate=0.5:7:2) to afford0.069 g (67%) of the title compound as an off-white solid. M.p.=156-158°C. 400 MHz ¹H NMR (DMSO-d₆ at 60° C.) δ: 11.08 (s, 1H), 8.70 (br. s,1H), 8.11 (d, J=4.8 Hz, 1H), 7.87 (s, 1H), 7.77-7.74 (m, 2H), 7.71-7.59(m, 3H), 7.59-7.56 (m, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.41 (d, J=4.4 Hz,1H), 7.13 (d, J=7.6 Hz, 1H), 6.40 (d, J=5.2 Hz, 1H), 3.93 (br. s, 1H),3.74-3.71 (m, 1H), 3.48-3.45 (m, 1H), 2.48-2.45 (m, 1H), 2.33 (t, J=7.6Hz, 1H), 2.15 (s, 3H), 1.89-1.82 (m, 2H), 1.59-1.56 (m, 1H), 1.39-1.34(m, 1H); LCMS: 608 [M+H].

Example 19 Preparation of3-{5-[2-([(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl]amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzaldehydeoxime 19a: Preparation of3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzaldehyde

To a solution of3-(5-{2-[(R)-1-(4-chloro-benzenesulfonyl)-piperidin-3-ylamino]-pyrimidin-4-yl}-imidazo[2,1-b]thiazol-6-yl)-N-methoxy-N-methyl-benzamide(0.05 g, 0.078 mmol) in anhydrous tetrahydrofuran (THF) (3.0 mL) at 0°C. was added a solution of lithium aluminum hydride (LAH) (2.0 M in THF)(0.078 mL, 0.15 mmol). The mixture was stirred at 0° C. for 30 minutes,then quenched with methanol (0.5 mL), diluted with dichloromethane (5mL), washed with a solution of 10% aqueous potassium sodium tartrate (5mL), water (5 mL), dried over sodium sulfate and concentrated. Productwas purified by flash chromatography on silica gel(methanol:dichloromethane:ethylacetate=0.5:7:2) to afford 0.033 g (73%)of the title compound as a pale yellow solid. M.p.=124-126° C.; 400 MHz¹H NMR (DMSO-d₆ at 60° C.) δ: 10.06 (s, 1H), 8.70 (br. s, 1H), 8.14-8.12(m, 2H), 7.96-7.91 (m, 2H), 7.77-7.74 (m, 2H), 7.70-7.64 (m, 3H), 7.43(d, J=4.4 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.39 (d, J=5.2 Hz, 1H), 3.93(bs, 1H), 3.74-3.71 (m, 1H), 3.48-3.45 (m, 1H), 2.49-2.4 (m, 1H), 2.35(t, J=10.8 Hz, 1H), 1.89-1.82 (m, 2H), 1.60-1.56 (m, 1H), 1.39-1.32 (m,1H).LCMS: 580 [M+H].

19b: Preparation of3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzaldehydeoxime

To a mixture3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzaldehyde(0.81 g, 0.14 mmol) and hydroxylamine hydrochloride (0.0107 g, 0.154mmol.) in methanol (2.0 mL) was added 0.2 mL of acetic acid. The mixturewas heated at 50° C. for 2 hours. After cooled to room temperature, themixture was diluted with dichloromethane (10 mL), washed with saturatedaqueous sodium bicarbonate (5 mL×3), water (5 mL), dried over sodiumsulfate and concentrated. Product was purified by flash chromatographyon silica gel (methanol:dichloromethane:ethylacetate=0.5:7:2) to afford0.051 g (61%) of the title compound as an off-white solid. M.p.=238-240°C. 400 MHz ¹H NMR (DMSO-d, at 60° C.) 11.14 (s, 1H), 8.70 (bs, 1H), 8.17(s, 1H), 8.11 (d, J=5.6 Hz, 1H), 7.8 (s, 1H), 7.77-7.74 (m, 2H),7.68-7.64 (m, 3H), 7.60-7.57 (m, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.41 (d,J=4.4 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.40 (d, J=5.2 Hz, 1H), 3.93 (br.s, 1H), 3.74-3.71 (m, 1H), 3.48-3.45 (m, 1H), 2.5-2.4 (m, 1H), 2.33 (t,J=10.4 Hz, 1H), 1.89-1.82 (m, 2H), 1.59-1.56 (m, 1H), 1.40-1.32 (m, 1H).LCMS: 594 [M+H].

Example 20 Preparation of(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)methanol

To a mixture3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzaldehyde(0.20 g, 0.346 mmol) in anhydrous tetrahydrofuran (THF) (5.0 mL) at roomtemperature was added a solution of lithium aluminum hydride (LAH) (2.0M in THF) (0.346 mL, 0.692 mmol). The mixture was stirred for one hour,then quenched with methanol (1.0 mL), diluted with dichloromethane (50mL) and 30 mL of water. Organic layer was separated and the water layerwas extracted with dichloromethane (50 mL×2). Organic layer wascombined, dried over sodium sulfate and concentrated. Product waspurified by flash chromatography on silica gel(methanol:dichloromethane:ethylacetate=0.5:7:2) to afford 0.142 g (71%)of the title compound as an off-white solid. M.p.=150-155° C. 400 MHz ¹HNMR (DMSO-d₆ at 60° C.) δ: 8.75 (bs, 1H), 8.12 (d, J=5.6 Hz, 1H),7.77-7.74 (m, 2H), 7.67-7.65 (m, 2H), 7.56 (s, 1H), 7.44-7.36 (m, 4H),7.11 (d, J=7.2 Hz, 1H), 6.39 (d, J=5.6 Hz, 1H), 5.07 (t, J=5.6 Hz, 1H),4.55 (d, J=6.0 Hz, 2H), 3.29 (br. s, 1H), 3.73 (d, J=7.2 Hz, 1H), 3.48(d, J=11.2 Hz, 1H), 2.5-2.43 (m, 1H), 2.35 (t, J=10.0 Hz, 1H), 1.91-1.82(m, 2H), 1.60-1.57 (m, 1H), 1.40-1.32 (m, 1H). LCMS: 581 [M+H].

Example 21 Preparation of4-{6-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]imidazo[2,1-b][1,3]thiazol-5-yl}-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine21a: Preparation of(R)-3-(4-{6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-imidazo[2,1-b]thiazol-5-yl}-pyrimidin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester

To mixture of hydroxylamine hydrochloride (0.030 g, 0.439 mmol) andsodium carbonate (0.021 g, 0.200 mmol) in water (0.40 mL) was addedtert-butyl(3R)-3-({4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate(0.200 g, 0.399 mmol) and ethanol (1.6 mL). The resulting mixture washeated at 80° C. for 4 hours and then solvent was removed. Residue wasdried under vacuum at 45° C. overnight. It was used for next reactionwithout further purification. The dried residue was dissolved inanhydrous N,N-demethylformamide (DMF) and acetic anhydride (0.041 mL,0.419 mmol) was added. The resulting mixture was heated at 120° C. for 3hours, cooled to room temperature, diluted with dichloromethane (10 mL),washed with water (5 mL×3), dried over sodium sulfate and concentrated.Product was purified by flash chromatography on silica gel eluting with80% ethyl acetate in hexane to afford 0.169 g (76%) of the titlecompound as a yellow solid. M.p.=110-112° C. 400 MHz ¹H NMR (DMSO-d₆ at60° C.) δ: 8.72 (bs, 1H), 8.25-8.24 (m, 1H), 8.12 (d, J=5.2 Hz, 1H),8.06-8.03 (m, 1H), 7.83-7.80 (m, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.44 (d,J=4.4 Hz, 1H), 7.17 (d, J=7.2 Hz, 1H), 6.44 (d, J=5.6 Hz, 1H), 3.95 (bs,1H), 3.81-3.78 (m, 1H), 3.68 (bs, 1H), 2.96 (bs, 2H), 2.00-1.97 (m, 1H),1.82-1.77 (m, 1H), 1.64-1.56 (m, 1H), 1.50-1.40 (m, 1H), 1.34 (s, 9H);LCMS: 559 [M+H].

21b: Preparation of4-{6-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]imidazo[2,1-b][1,3]thiazol-5-yl}-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine

((R)-3-(4-{6-[3-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-imidazo[2,1-b]thiazol-5-yl}-pyrimidin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (0.15 g, 0.269 mmol) was dissolved in 2 mL ofethyl acetate and treated with 2 ml of 3.0 M HCl in ethyl acetate atroom temperature (RT) overnight. Solid product was filtered, washedethyl acetate and dried under vacuum overnight to provide 0.135 g (100%)of the title compound as a yellow solid. M.p.=203-207° C. 400 MHz ¹H NMR(DMSO-d₆ at 60° C.) δ 9.35 (br. s, 1H), 8.21 (s, 1H), 8.12 (d, J=6.0 Hz,1H), 8.0 (d, J=7.6 Hz, 1H), 7.82-7.80 (m, 1H), 7.67 (t, J=8.2 Hz, 1H),7.54 (s, 10H), 6.90 (bs, 1H), 6.48 (d, J=5.6 Hz, 1H), 4.2 (br. s, 1H),3.40 (d, J=10.8 Hz, 1H), 3.13 (d, 1H), 2.92-2.87 (m, 2H), 2.65 (s, 31),2.00-1.97 (m, 1H), 1.96-1.89 (m, 1H), 1.89-1.80 (bs, 1H), 1.64-1.57 (m,1H); LCMS: 459 [M+H]. calc. for C₂₃H₂₂N₈OS 2.3 HCl: C, 50.93; H, 4.52;N, 20.66. found C, 50.93; H, 4.42; N, 19.30.

Example 22 Preparation of3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenylcarbamate

A solution of3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol(0.15 g, 0.26 mmol) in anhydrous tetrahydrofuran (10 ml, dissolved byslow warming) was treated with chlorosulfonyl isocyanate (34 ul, 1.5 eq)at room temperature. After 30 min the mixture was again treated withchlorosulfonyl isocyanate (34 ul, 1.5 eq) and stirred for 10 min.Solvent was removed under reduced pressure and the residue was purifiedby preparative HPLC (using TFA as modifier). Pure fractions werecollected and dried to give product as TFA salt (0.03 g, 19%).M.p.=118-120° C. 400 MHz ¹H NMR (DMSO-d₆ at 60° C.) δ: 8.78 (br. s, 1H),8.12 (d, J=5.6 Hz, 1H), 7.78-7.75 (m, 2H), 7.68-7.66 (m, 2H), 7.31 (m,1H), 7.40 (m, 1H), 7.25 (m, 1H), 7.15 (tt, J=2.0 and 7.4 Hz, 1H), 6.9(br m, 1H), 6.48 (d, J=5.6 Hz, 1H), 3.97 (br. s, 1H), 3.72 (dd, J=11.2and 4.4 Hz, 1H), 3.46 (d, J=11.6 Hz, 1H), 2.51 (m, 1H), 2.36 (t, J=9.6Hz, 1H), 1.91-1.83 (m, 2H), 1.65-1.5 (m, 1H), 1.44-1.38 (m, 1H). LCMS:611 [M+H]. Calc. for C₂₇H₂₄N₇O₄S₂Cl 1.84 TFA: C, 44.94; H, 3.18; N,11.96. found C, 44.93; H, 3.3; N, 11.46.

Example 23 Preparation of3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenylsulfamate

A solution of3-{(5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol(0.10 g, 0.176 mmol) in DMA (2.0 ml) was treated with sulfamoyl chloride(3-4 eq) in portions and monitor reaction for completion. After thereaction was complete dimethyl acetamide was removed under reducedpressure. Residue was taken in methanol (2.0 ml) and purified bypreparative HPLC (using TFA as modifier). Pure fractions were collectedand dried to give product as TFA salt (0.06 g, 53%). M.p.=133-35° C. 400MHz H NMR (DMSO-d₆ at 60° C.) δ: 8.67 (br, 1H), 8.13 (d, J=5.2 Hz, 1H),7.90 (brs, 2H), 7.77 (d, J=9.2 Hz 2H), 7.67 (d, J=9.2 Hz, 2H), 7.57 (m,1H), 7.52 (m, 1H), 7.43 (d, J=4.4 Hz, 1H), 7.35-7.33 (m, 1H), 7.20 (m,1H), 6.50 (d, J=5.2 Hz, 1H), 3.97 (br. s, 1H), 3.73 (m, 1H), 3.46 (d,J=10.8 Hz, 1H), 2.52 (m, 1H), 2.35 (t, J=10.8 Hz, 1H), 1.91-1.83 (m,2H), 1.59 (m, 1H), 1.43-1.35 (m, 1H). LCMS: 647 [M+H]. Calc. forC₂₆H₂₄N₇O₅S₃Cl.5.7 TFA: C, 34.66; H, 2.31; N, 7.56. found C, 35.08; H,1.78; N, 9.36.

Example 24 Measurement of RAF Activity

Materials: The RAF kinases and the anti-phospho MEK1/2 antibody werefrom Upstate (Charlottesville, Va.). The RAF substrate used was fulllength N-terminal GST-MEK-1, which was expressed in E. coli and purifiedin-house by HPLC. All proteins were aliquoted and stored at −80° C.Superblock™ in phosphate buffered saline (PBS) blocking reagent was formPierce (cat. #37515). ATP was from Roche (cat. # 19035722). AlkalinePhosphatase-tagged goat anti-rabbit antibody was from Pierce (cat. #31340).

Methods: All RAF biochemical assays were performed using an assay buffercontaining 20 mM MOPS, 5 mM EGTA, 37.5 mM MgCl₂, 1 mM DTT and 50 μM ATP.There was 6.25 ng/well mutant B-RAF and 7.5 ng/well MEK-1 in the finalassay conditions. Compounds were serially diluted in assay buffercontaining 1% DMSO and 20 μL of test compound at a concentration 3-foldmore than the final concentration, and were added to a polypropyleneV-well reaction plate. Vehicle control wells received buffer only withDMSO at equivalent concentrations to the test wells. In rapidsuccession, 20 μl of substrate was added (0.45 ng/μl MEK-1), followed by20 μl of enzyme (0.375 ng/μl mutant B-RAF). These reaction plates wereincubated at room temperature for 30 minutes. Capture of MEK-1 wasinitiated by transferring 50 μL of the reaction mixture to a NuncMaxisorp™ microplate that is designed for non-specific protein capture.After 30 minute capture of MEK-1 at room temperature, this plate waswashed with TBST (6×200 μL/well) to fully terminate the reaction. Theplate was then blocked for 1 hour by the addition of 100 μl/well ofSuperblock™ in phosphate buffered saline (PBS) blocking reagent. Platewas again washed with TBST (6 times with 200 μL/well), followed by theaddition of 70 μL/well of Upstate anti-phospho MEK 1/2 diluted 1:1000 inPierce Superblock (PBS). After a 60 minute incubation, this plate waswashed with TBST (6 times with 200 μL/well), and 70 μL of the secondaryantibody (Pierce Alkaline Phosphatase tagged goat anti-rabbit) preparedat 1:4000 in Superblock, were added. After a 45 minute incubation atroom temperature, the wells of the microplate were washed with TBST (6times with 200 μL/well), and thereafter 100 μl/well of Attophos™fluorescent alkaline phosphatase substrate was added according to themanufacturer's instructions (JBL Scientific). Fluorescence was read on aPerkin Elmer Envision multilabel reader, using the following filters:Excitation Filter: CFP430 nM, Emission Filter: Emission Filter 579 nM.

Example 25

Compounds of the present invention have been screened for their abilityto inhibit all isoforms, both wild-type and mutant of RAF kinases(A-RAF, B-RAF and C-RAF) in general, and the mutant B-RAF (V600E) inparticular in human cancer cells. A375 is a human melanoma cell linethat harbors the most common B-RAF mutation-V600E found in humancancers. The ability of compounds to inhibit RAF kinases in this assayis correlated with the reduction of MEK and ERK phosphorylation, and istherefore a direct indicator of potential in vivo therapeutic activity.

Materials: A375 cells from ATCC were maintained at 37° C., 5% CO₂ inDMEM media supplemented with 10% fetal bovine serum,penicillin/streptomycin and fungizone. (Invitrogen)

Methods: Test compounds were dissolved and diluted 1:1000 in DMSO. A375cells were seeded in six-well tissue culture plates at 5-8×10⁵ per welland cultured at 37° C. for 24 h. Cells were incubated with compounds forone hour before being lysed in EPage™ loading buffer (Invitrogen).Lysates were electrophoresed on 8% EPage™ gels and transferred topolyvinylidene difluoride membranes. After incubations with primary andsecondary antibodies, the immunostained proteins were detected andquantitated by an Odyssey infrared imager (Li-cor). Analysis wasperformed by non-linear regression to generate a dose response curve.The calculated IC₅₀ value was the concentration of the test compoundthat causes a 50% decrease in phospho-MEK and phospho-ERK levels. Theprimary antibodies used were anti-MEK (Stressgen), anti-ERK (BDBiosciences), anti-phospho-ERK and anti-phospho-MEK (Cell Signaling).The secondary antibodies used were IRDYE800 anti-rabbit, IRDYE 800anti-mouse (Rockland), AlexaFluor680 anti-mouse and AlexaFluoro680anti-rabbit (Invitrogen).

Compounds of the present invention reduce the levels of phospho-MEK andphospho-ERK through the inhibition of RAF kinases. The RAF/MEK/ERKpathway inhibition data for certain compounds of the present inventionare shown in FIGS. 5 and 6.

Example 26

Compounds of the present invention have been tested for activity againsta variety of cancer cell lines. The ability of compounds to inhibit cellgrowth in this assay is correlated with the reduction of dehydrogenaseenzyme activity found in metabolically active cells.

Materials: A375, Colo-205, DLD1, SK-MEL-2, SK-MEL-28 and SW480 cellsfrom ATCC were maintained at 37° C., 5% CO₂ in DMEM media supplementedwith 10% fetal bovine serum, penicillin/streptomycin and fungizone(Invitrogen). NCM460 (Incell), a normal colon epithelial cell line, andhuman mammary epithelial cells (Cambrex) were maintained at 37° C., 5%CO₂ in DMEM and HEBM media (Cambrex), respectively.

Methods: Test compounds were dissolved and diluted to 300× in DMSO thendiluted 1:40 in DMEM. Cells were seeded into 96-well tissue cultureplates at 2-5×10³ per well and cultured at 37° C. for 24 h. Cells wereincubated with test compounds for 72 hours followed by incubation withtetrazolium compound(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt; MTS) and the electron coupling reagent, phenazinemethosulfate (PMS) for 4 hr. MTS was chemically reduced by dehydrogenasein cells into formazan. The measurement of the absorbance of theformazan was assessed using an ENVISION™ (Perkin Elmer) microplatereader at 492 nm. The calculated IC₅₀ value is the concentration of thetest compound that causes a 50% decrease in the absorbance.

Compounds of the present invention inhibit the growth of a variety ofcancer cells. The data for certain compounds of the invention are shownin Table 1.

TABLE 1 IC₅₀ values of compound in various normal and cancer cell lines(units in μM) SKMEL2 DLD1 SW480 HMEC NCM460 A375 Colo205 SKMEL28 NRASKRAS KRAS Compound # Normal Normal B-RAF (V600E) B-RAF (V600E) B-RAF(V600E) (Q61R) (G13D) (G12V) 289 1.24 4.17 0.15 0.18 0.67 0.99 3.08 2.97105 2.72 6.68 0.31 0.38 0.48 1.1 4.73 1.28 267 1.07 2.05 0.27 0.19 0.380.87 1.76 2.13 112 2.24 4.71 0.27 0.33 0.86 0.91 3.33 2.74 268 0.72 2.540.37 0.36 0.8 1.33 4.03 4.4

TABLE 2 Exemplary compounds of the invention Melting Mutant B- point RAFIC₅₀ Cmpd (° C.) (uM) or # Structure IUPAC name or LCMS % inhibition 1

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[1-(methylsulfonyl)piperidin-3- yl]pyrimidin-2-amine 208-209 62 @ 10 uM 2

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-{1-[(4-fluorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 196-197 0.458 3

N-[1-(4-fluorobenzoyl)piperidin-3- yl]-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine 226-22845 @ 10 uM 4

N-[1-(4-fluorobenzyl)piperidin-3- yl]-4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- amine 131-133 55 @ 10 uM 5

N-(1-ethylpiperidin-3-yl)-4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- amine 115-117 54 @ 10 uM 6

N-ethyl-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2 yl}amino)piperidine-1- carboxamide128-130 54 @ 10 uM 7

N-(4-fluorophenyl)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide221-223 49 @ 10 uM 8

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-fluorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 145-148 0.023 9

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-{(3S)-1-[(4-fluorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 141-143 2.94 10

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3S)-piperidin-3-yl]pyrimidin-2-amine 208-210 51 @ 10 uM 11

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{(3R)-1-[(4-fluorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 135-138 0.207 12

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine 184-186 46 @ 10 uM 13

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[(3S)-piperidin-3-yl]pyrimidin-2-amine 202-205 30 @ 10 uM 14

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{(3S)-1-[(4-fluorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 115-117 >3.0 15

(3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-phenylpiperidine-1-carboxamide 141-144 28 @ 10 uM 16

(3R)-N-butyl-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide108-111 44 @ 10 uM 17

(3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-(4-methylphenyl)piperidine-1- carboxamide 129-132 16 @ 10 uM 18

(3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-(2-phenylethyl)piperidine-1- carboxamide 105-108 18 @ 10 uM 19

(3R)-N-cyclohexyl-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide130-132 46 @ 10 uM 20

(3R)-N-benzyl-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide116-120 24 @ 10 uM 21

(3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-(4-methoxyphenyl)piperidine-1- carboxamide 123-127 53 @ 10 uM 22

(3R)-N-(4-fluorophenyl)-3-({4-[6- (4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide134-137 35 @ 10 uM 23

(3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-(tetrahydro-2H-pyran-2-yl)piperidine-1- carboxamide 140-143 48 @ 10 uM 24

(3R)-N-[4- (dimethylamino)phenyl]-3-({4-[6- (4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide145-148 60 @ 10 uM 25

(3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-(2-furylmethyl)piperidine-1- carboxamide 112-115 35 @ 10 uM 26

N-[(3R)-1-benzoylpiperidin-3-yl]- 4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- amine 131-133 0.195 27

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[(3R)-1-(4-methoxybenzoyl)piperidin-3- yl]pyrimidin-2-amine 155-156 4.89 28

N-[(3R)-1-(4- fluorobenzoyl)piperidin-3-yl]-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine184-185 0.184 29

N-{(3R)-1-[(4- chlorophenoxy)acetyl]piperidin-3- yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 102-1031.82 30

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[(3R)-1-(methoxyacetyl)piperidin-3- yl]pyrimidin-2-amine 161-162 0.711 31

N-[(3R)-1- (cyclohexylcarbonyl)piperidin-3- yl]-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 129-1312.95 32

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[(3R)-1-isonicotinoylpiperidin-3- yl]pyrimidin-2-amine 196-198 0.362 33

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[(3R)-1-(2-furoyl)piperidin-3-yl]pyrimidin-2- amine 110-112 2.17 34

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[(3R)-1-propionylpiperidin-3-yl]pyrimidin- 2-amine 173-174 1.58 35

N-[(3R)-1-(aminoacetyl)piperidin- 3-yl]-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 225-23011 @ 10 uM 36

N-[(3R)-1-(2-amino-2- methylpropanoyl)piperidin-3-yl]-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine215-218 4.52 37

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[(3R)-1-L-prolylpiperidin-3-yl]pyrimidin-2- amine 210-212  >5.0 38

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-(3R)-1-(3-phenylpropanoyl)piperidin-3- yl]pyrimidin-2-amine 94-95 2.9 39

N-{(3R)-1-[4- (dimethylamino)benzoyl]piperidin- 3-yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 145-1460.477 40

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[(3R)-1-(3-methylbutanoyl)piperidin-3- yl]pyrimidin-2-amine 89-90 0.142 41

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[(3R)-1-(morpholin-4-ylcarbonyl)piperidin- 3-yl]pyrimidin-2-amine 102-105 38 @10 uM 42

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[(3R)-1-(phenylsulfonyl)piperidin-3- yl]pyrimidin-2-amine 143-144 68 @ 10 uM 43

N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 146-1470.143 44

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{(3R)-1-[(4-methoxyphenyl)sulfonyl]piperidin- 3-yl}pyrimidin-2-amine 233-234 45 @ 10uM 45

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{(3R)-1-[(4-methylphenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 194-195 0.59 46

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-((3R)-1-{[3-(trifluoromethyl)phenyl]sulfonyl} piperidin-3-yl)pyrimidin-2-amine125-127 19 @ 10 uM 47

N-{(3R)-1-[(3-chloro-4- fluorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 135-1360.963 48

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{(3R)-1-[(4-isopropylphenyl)sulfonyl]piperidin- 3-yl}pyrimidin-2-amine 199-200 3.0249

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-((3R)-1-{[4-(trifluoromethoxy)phenyl]sulfonyl} piperidin-3-yl)pyrimidin-2-amine164-165 32 @ 10 uM 50

N-{(3R)-1-[(3- chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 165-16635 @ 10 uM 51

N-{(3R)-1-[(3,5- dichlorophenyl)sulfonyl]piperidin- 3-yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 173-17425 @ 10 uM 52

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{(3R)-1-[(3-fluorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 134-135 55 @ 10uM 53

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{(3R)-1-[(2-methylphenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 155-156 42 @ 10uM 54

N-{(3R)-1-[(2,6- difluorophenyl)sulfonyl]piperidin- 3-yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimdin-2- amine 192-19347 @ 10 uM 55

4-{[(3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}benzonitrile 144-145 0.63 56

N-((3R)-1-{(3,5- bis(trifluoromethyl)phenyl]sulfonyl}piperidin-3-yl)-4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- amine 185-186 57 @ 10 uM 57

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{(3R)-1-[(3-methoxyphenyl)sulfonyl]piperidin- 3-yl}pyrimidin-2-amine 188-190 34 @ 10uM 58

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-((3R)-1-{[4-(trifluoromethyl)phenyl]sulfonyl} piperidin-3-yl)pyrimidin-2-amine153-154 0.403 59

4-{[(3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl)pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}benzoic acid 300 0.576 60

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{(3R)-1-[(4-phenoxyphenyl)sulfonyl]piperidin- 3-yl}pyrimidin-2-amine 279-280 15 @ 10uM 61

N-{(3R)-1-[(5-chloro-2- methoxyphenyl)sulfonyl]piperidin- 3-yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 173-17437 @ 10 uM 62

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine 191-194 45 @ 10 uM 63

3-(4-{[(3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}phenyl)propanoic acid 268-269 0.441 64

N-(5-{[(3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}-4-methyl-1,3-thiazol-2- yl)acetamide 176-177 58 @ 10 uM 65

N-{(3R)-1-[(2,4-dimethyl-1,3- thiazol-5-yl)sulfonyl]piperidin-3-yl}-4-[6-(4- fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-amine 220-222 42 @ 10 uM 66

N-{(3R)-1-[(1,2-dimethyl-1H- imidazol-4-yl)sulfonyl]piperidin-3-yl}-4-[6-(4- fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-amine 141-143 70 @ 10 uM 67

(3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-[5-methyl-2-(trifluoromethyl)-3- furyl]piperidine-1-carboxamide 120-122 29 @ 10 uM68

(3R)-N-(cyclohexylmethyl)-3-({4- [6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide118-120 42 @ 10 uM 69

(3R)-N-(2,4-dimethoxyphenyl)-3- ({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide113-116 42 @ 10 uM 70

(3R)-N-(5-chloro-2- methoxyphenyl)-3-({4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidine-1- carboxamide 127-130 49 @ 10 uM 71

(3R)-N-[2-(4-fluorophenyl)ethyl]- 3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide114-116 16 @ 10 uM 72

(3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-[(1R)-1-phenylethyl]piperidine-1- carboxamide 121-122 53 @ 10 uM 73

(3R)-N-(3,4-difluorophenyl)-3-({4- [6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide132-134 37 @ 10 uM 74

(3R)-N-(2-fluorophenyl)-3-({4-[6- (4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide112-115 35 @ 10 uM 75

(3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-(2-methoxy-4-nitrophenyl)piperidine-1- carboxamide 154-156 >10 76

(3R)-N-(4-fluorobenzyl)-3-({4-[6- (4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide111-113 36 @ 10 uM 77

4-[6-(3- methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine 220-225 1.81 78

4-[6-(3,4- difluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine 195-198 1.26 79

4-[6-(4-fluorophenyl)-2- methylimidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3- yl]pyrimidin-2-amine 206-208 67 @ 10 uM 80

(3R)-N-benzyl-3-({4-[6-(3- methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide108-110 40 @ 10 uM 81

(3R)-N-(2-furylmethyl)-3-({4-[6-(3- methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide119-121 50 @ 10 uM 82

N-{(3R)-1-[(4- fluorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(3-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine143-144 0.192 83

N-[(3R)-1-(4- methoxybenzoyl)piperidin-3-yl]-4-[6-(3-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine130-132 >3.0 84

(3R)-N-[4- (dimethylamino)phenyl]-3-({4-[6-(3-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1- carboxamide 127-129 19 @ 10 uM 85

4-[6-(3,4- difluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4- fluorophenyl)sulfonyl]piperidin-3-yl}pyrimidin-2-amine 128-131 0.058 86

(3R)-3-({4-[6-(3,4- difluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)-N-[4-(dimethylamino)phenyl]piperidine- 1-carboxamide 135-137 54 @ 10 uM 87

(3R)-N-benzyl-3-({4-[6-(3,4- difluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide107-110 53 @ 10 uM 88

(3R)-3-({4-[6-(3,4- difluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)-N-(2-furylmethyl)piperidine-1- carboxamide 101-102 54 @ 10 uM 89

4-[6-(3,4- difluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-1-(4- methoxybenzoyl)piperidin-3-yl]pyrimidin-2-amine 121-122 40 @ 10 uM 90

(3R)-N-benzyl-3-({4-[6-(4- fluorophenyl)-2-methylimidazo[2,1-b][1,3]thiazol- 5-yl]pyrimidin-2-yl}amino)piperidine-1- carboxamide 135-137 34 @ 10 uM 91

4-[6-(4-fluorophenyl)-2- methylimidazo[2,1-b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4- fluorophenyl)sulfonyl]piperidin-3-yl}pyrimidin-2-amine 245-246 0.352 92

4-[6-(4-fluorophenyl)-2- methylimidazo[2,1-b][1,3]thiazal-5-yl]-N-[(3R)-1-(4- methoxybenzoyl)piperidin-3- yl]pyrimidin-2-amine200-201  5 @ 10 uM 93

(3R)-3-({4-[6-(4-fluorophenyl)-2- methylimidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)-N-(2- furylmethyl)piperidine-1- carboxamide113-115 61 @ 10 uM 94

(3R)-N-[4- (dimethylamino)phenyl]-3-({4-[6- (4-fluorophenyl)-2-methylimidazo[2,1-b][1,3]thiazol- 5-yl]pyrimidin-2-yl}amino)piperidine-1- carboxamide 193-194 >3.0 95

N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(3-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine127-128 0.147 96

N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(4-fluorophenyl)-2- methylimidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine 273-274 0.026 97

4-[6-(2-naphthyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine 202-205 0.314 98

N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine 154-1550.036 99

4-[6-(2,3-dihydro-1,4- benzodioxin-6-yl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)- piperidin-3-yl]pyrimidin-2-amine 210-21529 @ 10 uM 100

4-[6-(4-chloro-3- methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}pyrimidin-2-amine 149-151 40 @ 10 uM 101

2-chloro-5-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 163-1640.011 102

4-[6-(2- methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine 237-239 1.26 103

N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(3-methoxyphenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 115-11848 @ 10 uM 104

3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]oxazol-6- yl}phenol 205-2100.038 105

N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(2-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine151-153 0.25 106

4-[6-(4- methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine 189-191 27 @ 10 uM 107

2-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 154-1550.033 108

N-[(3R)-1-(4- fluorobenzoyl)piperidin-3-yl]-4-[6-(3-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine88-90 73 @ 10 uM 109

4-[6-(3- methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3R)-1-(3-methylbutanoyl)piperidin-3- yl]pyrimidin-2-amine 85-87 >3.0 110

4-{5-[(2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol179-180 >5.0 111

4-{[(3R)-3-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}benzonitrile 178-180 0.028 112

N-[(3R)-1-isonicotinoylpiperidin-3- yl]-4-[6-(3-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine133-135 >5.0 113

3-[5-(2-{[(3R)-1-(4- fluorobenzoyl)piperidin-3- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 155-157 3.84 114

N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(3,4-difluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine111-113 48 @ 3 uM  115

4-[6-(3- methoxyphenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine 172-175 >10 116

3-[5-(2-{[(3R)-1-(3- methylbutanoyl)piperidin-3- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 146-148 52 @ 10 uM 117

3-[5-(2-{[(3R)-1- isonicatinoylpiperidin-3- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 162-164 0.328 118

3-(4-{[(3R)-3-({4-[6-(3- methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}phenyl)propanoic acid 146-148 0.229 119

4-{[(3R)-3-({4-[6-(3- methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}benzoic acid >300 0.092 120

N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(3-nitrophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine 185-18755 @ 10 uM 121

4-{[(3R)-3-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}benzoic acid >300 0.002 122

4-[6-(3-aminophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 226-228 0.429123

N-(3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)acetamide 169-174 0.215 124

N~1~-(3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)glycinamide 208-212 2.96 125

3-(5-{2-[(3R)-piperidin-3- ylamino]pyrimidin-4-yl}imidazo[2,1-b][1,3]thiazol-6- yl)benzonitrile 205-207 19 @ 10 uM 126

3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzonitrile144-146 0.71 127

4-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzoic acid255-260 >3.0 128

ethyl 2-ethoxy-4-(5-{2-[(3R)- piperidin-3-ylamino]pyrimidin-4-yl}imidazo[2,1-b][1,3]thiazal-6- yl)benzoate 195-197 24 @ 10 uM 129

4-{[(3R)-3-({4-[6-(3- cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}benzoic acid 245-247 >3.0 130

ethyl 4-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}-2-ethoxybenzoate 138-140 1.09 131

N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(2-nitrophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine 155-1560.025 132

4-[6-(2-aminophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 155-157 0.444133

4-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}-2-hydroxybenzoic acid 228-229 0.84 134

4-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl)benzene-1,2-diol 195-197 0.024 135

N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(3,4-dimethoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine168-170 0.696 136

4-amino-N-(2-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)butanamide 206-208 >3.0 137

4-[6-(3- methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3S)-piperidin-3-yl]pyrimidin-2-amine 176-178 42 @ 10 uM 138

N~1~-(2-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl]phenyl)-beta-alaninamide 203-204 82 @ 10 uM 139

N-{(3S)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine125-127 41 @ 10 uM 140

3-{5-[(2-({(3S)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl)amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 158-1600.953 141

N~1~-(2-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)glycinamide 198-200 0.814 142

4-[6-(3- methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-{(3R)-[(3-methoxyphenyl)sulfonyl]piperidin- 3-yl}pyrimidin-2-amine 105-106 56 @ 10uM 143

3-{[(3R)-3-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}phenol 170-172 0.019 144

N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3- yl}-4-[(6-(2,5-dimethoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine128-131 69 @ 10 uM 145

2-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzene-1,4-diol 185-187 0.092 146

N-((3R)-1-{[(4R)-2,2-dimethyl-1,3- dioxolan-4-yl]methyl}piperidin-3-yl)-4-[6-(3- methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-amine 73-75 43 @ 10 uM 147

(2R)-3-[(3R)-3-({4-[6-(3- methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]propane-1,2-diol 106-108 >3.0 148

(2R)-3-[(3R)-3-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]propane-1,2-diol 185-187 >3.0 149

4-[6-(3- methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-methoxyphenyl)sulfonyl]piperidin- 3-yl}pyrimidin-2-amine 105-107 0.188150

3-{5-[2-({(3R)-1-[(4- hydroxyphenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol185-187 0.009 151

4-[6-(3- methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3R)-1-(methylsulfonyl)piperidin-3- yl]pyrimidin-2-amine 118-120 0.85 152

3-[5-(2-{[(3R)-1- (methylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 172-175 0.116 153

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-{1 -[(4-fluorophenyl)sulfonyl]piperidin-4- yl}pyrimidin-2-amine 259-260 0.078154

N-(1-ethylpiperidin-4-yl)-4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- amine 173-175 36 @ 10 uM 155

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-piperidin-4-ylpyrimidin-2-amine  282-286, 2.36 156

N-ethyl-4-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide110-112 0.428 157

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{1-[(4-fluorophenyl)sulfonyl]piperidin-4- yl}pyrimidin-2-amine 222-223 0.675158

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[1-(4-methoxybenzoyl)piperidin-4- yl]pyrimidin-2-amine 196-197 0.465 159

N-(1-benzoylpiperidin-4-yl)-4-[6- (4-fluorophenyl)imidazo(2,1-b][1,3]oxazol-5-yl]pyrimidin-2- amine 218-220 1.01 160

N-{1-[(4- chlorophenoxy)acetyl]piperidin-4- yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 209-2103.85 161

4-[6-(4-fluorophenyl)jmidazo[2,1- b][1,3]oxazol-5-yl]-N-[1-(quinolin-8-ylcarbonyl)piperidin-4- yl]pyrimidin-2-amine 254-256 1.57 162

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[1-(piperidin-4-ylcarbonyl)piperidin-4- yl]pyrimidin-2-amine 209-212 1.32 163

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[1-(methoxyacetyl)piperidin-4- yl]pyrimidin-2-amine 204-207 53 @ 10 uM 164

N-[1- (cyclohexylcarbonyl)piperidin-4- yl]-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 135-13638 @ 10 uM 165

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-(1-isonicotinoylpiperidin-4- yl)pyrimidin-2-amine 210-211 33 @ 10 uM 166

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[1-(2-furoyl)piperidin-4-yl]pyrimidin-2- amine 105-107 76 @ 10 uM 167

N-cyclohexyl-4-({4-[6-(4- fluorophenyl)imidazo(2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide168-169 4.71 168

N-butyl-4-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide155-156 1.11 169

4-({4-[6-(4- fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)-N-(2- phenylethyl)piperidine-1- carboxamide 119-120 0.266 170

N-benzyl-4-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide124-126 0.189 171

4-({4-[6-(4- fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)-N-phenylpiperidine-1- carboxamide 182-183 4.73 172

4-({4-[6-(4- fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)-N-(4- methylphenyl)piperidine-1- carboxamide 180-182 1.98 173

4-({4-[6-(4- fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)-N-(4- methoxyphenyl)piperidine-1- carboxamide 153-154 2.56 174

N-(4-fluorophenyl)-4-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide192-193 4.73 175

N-[4-(dimethylamino)phenyl]-4- ({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide225-227 0.066 176

4-({4-[6-(4- fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)-N-(2- furylmethyl)piperidine-1- carboxamide 118-121 0.082 177

4-({4-[6-(4- fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)-N-(tetrahydro-2H- pyran-2-yl)piperidine-1- carboxamide 184-1850.354 178

N-(3,5-dimethylisoxazol-4-yl)-4- ({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide208-210 19 @ 10 uM 179

N-{1-[(4- fluorophenyl)acetyl]piperidin-4- yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 209-21129 @ 10 uM 180

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[1-(3-methylbutanoyl)piperidin-4- yl]pyrimidin-2-amine 101-103 2.04 181

N-[1-(4-fluorobenzoyl)piperidin-4- yl]-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 204-2062.7 182

4-({4-[6-(4- fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)-N-[4- (trifluoromethyl)phenyl]piperidine- 1-carboxamide209-211 45 @ 10 uM 183

N-(cyclohexylmethyl)-4-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide127-130 3.61 184

N-[2-(4-fluorophenyl)ethyl]-4-({4- [6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide194-195 1.28 185

N-(tert-butyl)-4-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide134-138 1.58 186

4-({4-[6-(4- fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)-N-[5-methyl-2- (trifluoromethyl)-3-furyl]piperidine-1-carboxamide 195-200 16 @ 10 uM 187

N-(2-fluorophenyl)-4-({4-(6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide133-134 10 @ 10 uM 188

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-(1-propionylpiperidin-4-yl)pyrimidin- 2-amine 199-201 1.5 189

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[1-(3-phenylpropanoyl)piperidin-4- yl]pyrimidin-2-amine 144-146 1.94 190

N-[1-(aminoacetyl)piperidin-4-yl]- 4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- amine 204-205 1.15 191

N-[1-(2-amino-2- methylpropanoyl)piperidin-4-yl]-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine216-218 3.76 192

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-(1-L-prolylpiperidin-4-yl)pyrimidin-2- amine 198-202 1.45 193

N-(3,4-difluorophenyl)-4-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide187-188 1.23 194

N-(4-fluorobenzyl)-4-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide115-118 55 @ 10 uM 195

4-({4-[6-(4- fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)-N-[(1S)-1- phenylethyl]piperidine-1- carboxamide 121-123 56 @10 uM 196

(4S)-4-amino-5-[4-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]-5- oxopentanoicacid 161-164 3.32 197

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[1-(phenylsulfonyl)piperidin-4- yl]pyrimidin-2-amine 266-268 0.168 198

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{1-[(4-methylphenyl)sulfonyl]piperidin-4- yl}pyrimidin-2-amine 247-248 0.218199

N-{1-[(4- chlorophenyl)sulfonyl]piperidin-4- yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 229-2300.092 200

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{1-[(4-methoxyphenyl)sulfonyl]piperidin- 4-yl}pyrimidin-2-amine 234-236 0.115201

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{1-[(4-isopropylphenyl)sulfonyl]piperidin- 4-yl}pyrimidin-2-amine 235-237 0.42202

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-(1-{[3-(trifluoromethyl)phenyl]sulfonyl} piperidin-4-yl)pyrimidin-2-amine266-268 0.84 203

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-(1-{[4-(trifluoromethoxy)phenyl]sulfonyl} piperidin-4-yl)pyrimidin-2-amine230-232 0.521 204

N-{1-[(3-chloro-4- fluorophenyl)sulfonyl]piperidin-4- yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 218-2200.541 205

N-{1-[(3,5- dichlorophenyl)sulfonyl]piperidin- 4-yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 218-2200.981 206

N-{1-[(3- chlorophenyl)sulfonyl]piperidin-4- yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 225-2260.329 207

N-(1-{[3,5- bis(trifluoromethyl)phenyl]sulfonyl}piperidin-4-yl)-4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- amine 225-227 0.027 208

4-[6-(3- methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-piperidin-4-ylpyrimidin-2-amine 255-260 2.93 209

N-{1-[(4-amino-3,5,6- trichloropyridin-2-yl)carbonyl]piperidin-4-yl}-4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- amine 275-276 49 @ 10 uM 210

N-[1-(2,6- dimethoxybenzoyl)piperidin-4-yl]-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine253-254 38 @ 10 uM 211

N-{2-[4-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin- 2-yl}amino)piperidin-1-yl]-2-oxoethyl}acetamide 235-237 29 @ 10 uM 212

N-[2-[4-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin- 2-yl}amino)piperidin-1-yl]-1-(hydroxymethyl)-2- oxoethyl]acetamide 155-157 43 @ 10 uM 213

N-ethyl-4-({4-[6-(3- methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide124-125 2.04 214

N-{1-[(4- fluorophenyl)sulfonyl]piperidin-4- yl}-4-[6-(3-methoxyphenyl)imidazol[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine208-209 0.392 215

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-(1-{[(4-methylpyrimidin-2- yl)thio]acetyl}piperidin-4- yl)pyrimidin-2-amine219-220 40 @ 10 uM 216

N-[4-(dimethylamino)phenyl]-4- ({4-[6-(3- methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide127-128 58 @ 10 uM 217

4-[6-(3,4- difluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-{1-[(4-fluorophenyl)sulfonyl]piperidin-4- yl}pyrimidin-2-amine 258-259 48 @ 10uM 218

4-({4-[6-(3,4- difluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)-N-ethylpiperidine-1-carboxamide 221-222 1.22 219

4-[6-(4-fluorophenyl)-2- methylimidazo[2,1-b][1,3]thiazol-5-yl]-N-{1-[(4- fluorophenyl)sulfonyl]piperidin-4- yl}pyrimidin-2-amine238-239 0.051 220

N-ethyl-4-({4-[6-(4-fluorophenyl)- 2-methylimidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide217-218 0.428 221

4-[6-(3,4- difluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-{1-[4-(dimethylamino)benzoyl]piperidin- 4-yl}pyrimidin-2-amine 148-149 42 @ 10uM 222

N-{1-[4- (dimethylamino)benzoyl]piperidin- 4-yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 175-17745 @ 10 uM 223

4-[6-(3,4- difluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-piperidin-4- ylpyrimidin-2-amine 189-191 71 @ 10uM 224

4-[6-(4-fluorophenyl)-2- methylimidazo[2,1-b][1,3]thiazol-5-yl]-N-piperidin-4-ylpyrimidin-2- amine 267-268 70 @ 10 uM 225

N-[4-(dimethylamino)phenyl]-4- ({4-[6-(4-fluorophenyl)-2-methylimidazo[2,1-b][1,3]thiazol- 5-yl]pyrimidin-2-yl}amino)piperidine-1- carboxamide 228-230 38 @ 10 uM 226

4-({4-[6-(3,4- difluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)-N-[4-(dimethylamino)phenyl]piperidine- 1-carboxamide 205-206 61 @ 10 uM 227

N-{1-[(5-chloro-2- methoxyphenyl)sulfonyl]piperidin- 4-yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 156-15827 @ 10 uM 228

N-(5-{[4-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}-4-methyl-1,3-thiazol-2- yl)acetamide >300 40 @ 10 uM 229

4-{[4-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}benzoic acid 182-184 1.37 230

N-{1-[(2,4-dimethyl-1,3-thiazol-5- yl)sulfonyl]piperidin-4-yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 240-24250 @ 10 uM 231

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{1-[(3-methoxyphenyl)sulfonyl]piperidin- 4-yl}pyrimidin-2-amine 214-215 0.408232

N-ethyl-4-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)-N-methylpiperldine-1-carboxamide 104-107 56 @ 10 uM 233

N-benzyl-4-({4-[6-(3- methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide118-120 53 @ 10 uM 234

N-(2-furylmethyl)-4-({4-[6-(3- methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide127-128 0.825 235

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{1-[(2-methylphenyl)sulfonyl]piperidin-4- yl}pyrimidin-2-amine 263-265 30 @ 10uM 236

N-{1-[(2,6- difluorophenyl)sulfonyl]piperidin- 4-yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 252-25530 @ 10 uM 237

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{1-[(3-fluorophenyl)sulfonyl]piperidin-4- yl}pyrimidin-2-amine 215-218 85 @ 5uM  238

4-[6-(4-fluorophenyt)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{1-[(4-phenoxyphenyl)sulfonyl]piperidin- 4-yl}pyrimidin-2-amine 213-215 >10 239

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-(1-{[4-(trifluoromethyl)phenyl]sulfonyl} piperidin-4-yl)pyrimidin-2-amine231-233 52 @ 3 uM  240

4-{[4-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}benzonitrile 267-269 44 @ 10 uM 241

N-benzyl-4-({4-[6-(4- fluorophenyl)-2- methylimidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide 137-138 2.53 242

4-({4-[6-(4-fluorophenyl)-2- methylimidazo[2,1-b][1,3]-thiazol-5-yl]pyrimidin-2-yl}amino)-N-(2- furylmethyl)piperidine-1- carboxamide178-179 67 @ 10 uM 243

4-({4-[6-(3,4- difluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)-N-(2-furylmethyl)piperidine-1- carboxamide 159-160 76 @ 10 uM 244

4-[6-(2-naphthyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-piperidin-4-ylpyrimidin-2-amine 210-215 47 @ 10 uM 245

N-(1-{[4- (dimethylamino)phenyl]acetyl} piperidin-4-yl)-4-[6-(3-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine138-140 2.46 246

4-[3-methyl-6-(4- methylphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-piperidin-4- ylpyrimidin-2-amine 185-189 >10 247

4-[6-(4-nitrophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-piperidin-4-ylpyrimidin-2-amine 203-206 9 @ 3 uM 248

N-{1-[(1,2-dimethyl-1H-imidazol- 4-yl)sulfonyl]piperidin-4-yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine148-152 0.931 249

4-[6-(2,3-dihydro-1,4- benzodioxin-6-yl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-piperidin-4- ylpyrimidin-2-amine 231-235 58 @ 10uM 250

4-(6-biphenyl-4-ylimidazo[2,1- b][1,3]thiazol-5-yl)-N-piperidin-4-ylpyrimidin-2-amine 195-198 2 @ 3 uM 251

N-benzyl-4-({4-[6-(3,4- difluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide187-188 63 @ 10 uM 252

N-[4-(dimethylamino)phenyl]-4- ({4-[3-methyl-6-(4-methylphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1- carboxamide 133-135 >3.0 253

N-[4-(dimethylamino)phenyl]-4- ({4-[6-(4-nitrophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide185-188 >3.0 254

4-{[4-(6-biphenyl-4-ylimidazo[2,1- b][1,3]thiazol-5-yl)pyrimidin-2-yl]amino}-N-[4- (dimethylamino)phenyl]piperidine- 1-carboxamide141-145 >3.0 255

N-{1-[(4- chlorophenyl)sulfonyl]piperidin-4- yl}4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine 244-2450.696 256

4-({4-[6-(4- fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidine-1- carboxamide 185-190 >1.0 257

N-{1-[(4- chlorophenyl)sulfonyl]piperidin-4-yl}-4-[6-(4-fluorophenyl)-2- methylimidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine 148-149 0.073 258

4-{[4-({4-[6-(4-fluorophenyl)-2- methylimidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1- yl]sulfonyl}benzoic acid 195-1960.322 259

N-(4-{5-(2-({1-[(4- chlorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4- yl}imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)acetamide 175-178 >3.0 260

4-[6-(2,3-dihydro-1,4- benzodioxin-6-yl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-{1-[(4- fluorophenyl)sulfonyl]piperidin-4-yl}pyrimidin-2-amine 251-253 0.186 261

4-[6-(2- methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-piperidin-4-ylpyrimidin-2-amine 235-237 >3.0 262

N-{1-[(4- chlorophenyl)sulfonyl]piperidin-4- yl}-4-[6-(4-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyridimin-2- amine127-129 >3.0 263

N{1-[(4- chlorophenyl)sulfonyl]piperidin-4- yl}-4-[6-(3-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine215-216 >5.0 264

4-{5-[2-({1-[(4- chlorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 188-190 5 @ 10 uM 265

N-{1-[(4- chlorophenyl)sulfonyl]piperidin-4- difluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- amine 243-245 >3.0 266

3-{5-[2-({1-[(4- fluorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 175-1790.029 267

3-{5-[2-({1-[(4- chlorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 160-1700.031 268

N-ethyl-4-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide170-172 0.009 269

3-{5-[2-({1-[(4- chlorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzonitrile145-147 1.63 270

3-(4-{[4-({4-[6-(3- methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}phenyl)prapanoic acid 159-160 0.316 271

3-{5-[2-(piperidin-4- ylamino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzonitrile 218-220 58 @ 10 uM 272

methyl 3-(4-{[4-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}phenyl)propanoate 155-157 0.01 273

3-(4-{[4-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}phenyl)propanoic acid 179-180 0.01 274

N-{1-[(4- chlorophenyl)sulfonyl]piperidin-4- yl)-4-[6-(2-nitrophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine 258-2600.722 275

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3S)-pyrrolidin-3-yl]pyrimidin-2-amine 230-232 30 @ 10 uM 276

N-{(3S)-1-[(4- chlorophenyl)sulfonyl]pyrrolidin-3- yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine 190-19195 @ 10 uM 277

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3R)-pyrrolidin-3-yl]pyrimidin-2-amine 175-179 0.044 278

N-{(3R)-1-[(4- chlorophenyl)sulfonyl]pyrrolidin-3- yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine 191-19210 @ 10 uM 279

4-[6-(3- methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3R)-pyrrolidin-3-yl]pyrimidin-2-amine 171-173 36 @ 10 uM 280

N-{(3R)-1-[(4- chlorophenyl)sulfonyl]pyrrolidin-3- yl)-4-[6-(3-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine180-182 37 @ 10 uM 281

4-{[(3R)-3-({4-[6-(3- methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)pyrrolidin-1-yl]sulfonyl}benzoic acid 68-70 >3.0 282

4-{[(3R)-3-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)pyrrolidin-1-yl]sulfonyl}benzoic acid 210-212 0.522 283

3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]pyrrolidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 142-1431.6 284

3-(5-{2-[(3R)-pyrrolidin-3- ylamino]pyrimidin-4-yl}imidazo[2,1-b][1,3]thiazol-6- yl)benzonitrile 186-188 61 @ 10 uM 285

3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]pyrrolidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzonitrile165-167 35 @ 10 uM 286

N-{1-[(4- chlorophenyl)sulfonyl]azetidin-3- yl}-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazal-5-yl]pyrimidin-2- amine 129-1303 287

N-azetidin-3-yl-4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- amine 223-225 2.49 288

3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 174-1770.002 289

N-[1-(4-fluorobenzoyl)piperidin-4- yl]-4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine184-185 >10 290

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-{1-[(4-fluorophenyl)sulfonyl}piperidin-4- yl}pyrimidin-2-amine 256-257 0.078291

N-(1-acetylpiperidin-4-yl)-4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- amine 201-203 41 @ 10 uM 292

N-(1-ethylpiperidin-4-yl)-4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- amine 173-175 36 @ 10 uM 293

N-[1-(4-fluorobenzyl)piperidin-4- yl]-4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- amine 503 [M + H] 14 @ 10 uM 294

N-ethyl-4-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide210-212 0.041 295

N-(4-fluorophenyl)-4-({4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide158-160 49 @ 10 uM 296

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[1-(methylsulfonyl)piperidin-4- yl]pyrimidin-2-amine 473 [M + H] NT 297

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-piperidin-4-ylpyrimidin-2-amine 282-286 3 298

N-(1-acetylpiperidin-4-yl)-4-[6-(4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- amine 214 59 @ 10 uM 299

4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[1-(methylsulfonyl)piperidin-4- yl]pyrimidin-2-amine 206-208 55 @ 10 uM 300

4-[6-(2,4- difluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-piperidin-4- ylpyrimidin-2-amine 212-215 65 @ 10uM 301

4-[6-(2-chloro-4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-piperidin-4- ylpyrimidin-2-amine 216-218 39 @ 10uM 302

N-(1-acetylpiperidin-4-yl)-4-[6-(2- chlorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- amine 155-163 39 @ 10 uM 303

N-(1-acetylpiperidin-4-yl)-4-[6-(2- methylphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- amine 152-159 42 @ 10 uM 304

4-[6-(2-methylphenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-piperidin-4-ylpyrimidin-2-amine 217-220 56 @ 10 uM 305

N-(1-acetylpiperidin-4-yl)-4-[6-(2- chloro-4- fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- amine 143-145 47 @ 10 uM 306

N-piperidin-4-yl-4-{6-[3- (trifluoromethyl)phenyl]imidazo[2,1-b][1,3]oxazol-5-yl}pyrimidin-2- amine 176-180 32 @ 10 uM 307

4-[6-(2-chlorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-piperidin-4-ylpyrimidin-2-amine 216-220 55 @ 10 uM 308

4-[6-(2-methylphenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[1-(methylsulfonyl)piperidin-4- yl]pyrimidin-2-amine 121-123 45 @ 10 uM 309

N-[1-(methylsulfonyl)piperidin-4- yl]-4-{6-[3-(trifluoromethyl)phenyl]imidazo[2, 1-b][1,3]oxazol-5-yl}pyrimidin-2-amine 165-167 33 @ 10 uM 310

N-(1-acetylpiperidin-4-yl)-4-[6- (2,4-difluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- amine 255-258 33 @ 10 uM 311

4-[6-(2-chlorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[1-(methylsulfonyl)piperidin-4- yl]pyrimidin-2-amine 145-148 61 @ 10 uM 312

4-[6-(2-chloro-4- fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[1-(methylsulfonyl)piperidin-4- yl]pyrimidin-2-amine 210-212 73 @ 10 uM 313

4-[6-(2,5- dimethoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine 195-200 3 314

methyl 4-{[(3R)-3-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}benzoate 184-186 0.03 315

3-[5-(2-{[1- (cyclopropylsulfonyl)piperidin-4- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 166-171 0.011 316

1-(4-chlorophenoxy)-3-[4-({4-[6- (3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]propan-2- ol109-111 3 317

4-{[4-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}benzonitrile 224-226 0.022 318

3-{5-[2-({1-[3-(4-chlorophenoxy)- 2-hydroxypropyl]piperidin-4-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 130-1320.422 319

4-{[4-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}benzamide 242-250 0.018 320

4-{[(3R)-3-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}benzonitrile 178-180 0.01 321

3-{5-[2-({1-[(4- chlorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]oxazol-6- yl}phenol 175-1770.126 322

3-{5-[2-({1-[(4- fluorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]oxazol-6- yl}phenol 173-1760.046 323

N-[(4-chlorophenyl)sulfonyl]-4- ({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide204-208 1.22 324

N-[(4-chlorophenyl)sulfonyl]-4- ({4-[6-(3- methoxyphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide165-166 4 325

N-[(3R)-1- (cyclopropylsulfonyl)piperidin-3- yl]-4-[6-(3-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine107-115 4 326

4-[6-(3- methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[1-(methylsulfonyl)piperidin-4- yl]pyrimidin-2-amine 110-118 4 327

(3R)-N-(4-fluorophenyl)-3-({4-[6- (3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide120-122 4 328

(3R)-N-cyclohexyl-3-({4-[6-(3- methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide123-125 4 329

(3R)-N-(4-ethoxyphenyl)-3-({4-[6- (3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide122-124 4 330

(3R)-3-({4-[6-(3- methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)-N-(4-(methylthio)phenyl]piperidine-1- carboxamide 128-130 4 331

3-{5-[2-({(3R)-1-[3-(4- chlorophenoxy)-2- hydroxypropyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 130-1351.04 332

3-[5-(2-{[1- (methylsulfonyl)piperidin-4- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 220-226 0.01 333

3-(5-{2-[(3R)-piperidin-3- ylamino]pyrimidin-4-yl}imidazo[2,1-b][1,3]oxazol-6- yl)phenol 220-225 0.906 334

(3R)-3-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)-N-isopropylpiperidine-1-carboxamide 170-172 0.65 335

(3R)-N-(4-fluorophenyl)-3-({4-[6- (3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide160-162 3.26 336

N-[(4-chloropheriyl)sulfonyl]-4- ({4-[6-(3- hydroxyphenyl)imidazo[2,1-yl}amino)piperidine-1- b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1- carboxamide 185-189 1.05 337

4-[6-(3- methoxyphenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-piperidin-4-ylpyrimidin-2-amine 230-232 3.21 338

N-[1- (cyclopropylsulfonyl)piperidin-4- yl]-4-[6-(3-methoxyphenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 165-1666.99 339

3-[5-(2-{[1- (cyclopropylsulfonyl)piperidin-4- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6- yl]phenol 152-154 0.046 340

4-[6-(3- methoxyphenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[1-(methylsulfonyl)piperidin-4- yl]pyrimidin-2-amine 206-207 10 341

(2R)-2,3-dihydroxypropyl 4- {[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-yl)amino)piperidin-1- yl]sulfonyl}benzoate 182-184 0.033 342

3-[5-(2-{[1- (methylsulfonyl)piperidin-4- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6- yl]phenol 237-239 0.258 343

(3R)-N-(4-hydroxyphenyl)-3-({4- [6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide205-207 1.44 344

(3R)-3-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)-N-[4-(methylthio)phenyl]piperidine-1- carboxamide 172-174 2.45 345

3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}- N′-hydroxybenzenecarboximidamide 272-273 30 346

N-(3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)methanesulfonamide 170-172 0.88 347

1-(3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)-3-ethylurea 165-167 0.546 348

N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine142-143 0.105 349

N-[1- (cyclopropylsulfonyl)piperidin-4- yl]-4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine146-148 2.6 350

3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzamide168-170 0.14 351

4-({4-[6-(3- hydroxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)-N-isopropylpiperidine- 1-carboxamide 280-290 0.94 352

4-({4-[6-(3- hydroxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)-N-methylpiperidine-1- carboxamide 285-295 0.67 353

5-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}-2-fluorophenol 172-175 0.003 354

5-[5-(2-{[1- (cyclopropylsulfonyl)piperidin-4- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]- 2-fluorophenol 224-225 0.0003 355

4-({4-[6-(3- hydroxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)-N-propylpiperidine-1- carboxamide 235-240 1.79 356

N-cyclopentyl-4-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide282-295 2.54 357

N-butyl-4-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide265-270 3 358

4-(5-{2-[(3R)-piperidin-3- ylamino]pyrimidin-4-yl}imidazo[2,1-b][1,3]thiazol-6- yl)benzonitrile 215-216 30 359

ethyl 4-(5-{2-[(3R)-piperidin-3- ylamino]pyrimidin-4-yl}imidazo[2,1-b][1,3]thiazol-6- yl)benzoate 224-226 30 360

4-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b](1,3]thiazol-6- yl}benzonitrile241-244 2.47 361

ethyl 4-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzoate129-131 3.25 362

N-cyclohexyl-4-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidane-1- carboxamide190-200 3 363

3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}- N′-hydroxybenzenecarboximidamide 177-179 8 364

3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenylcarbamate 118-120 0.007 365

4-{6-[3-(5-methyl-1,2,4-oxadiazol- 3-yl)phenyl]imidazo[2,1-b][1,3]thiazol-5-yl}-N-[(3R)- piperidin-3-yl]pyrimidin-2-amine 203-2070.03 366

3-{5-[2-({(3R)-1-[(1-methyl-1H- imidazol-4-yl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl}imidazo[2,1-b][1,3]thiazol-6- yl}phenol 183-1910.011 367

3-[5-(2-{[(3R)-1-(3- thienylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 180-185 0.003 368

3-[5-(2-{[(3R)-1- (isopropylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 165-170 >3 369

3-[5-(2-{[(3R)-1- (benzylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 165-170 >3 370

3-[5-(2-{[(3R)-1- (propylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 150-155 1.2 371

3-[5-(2-{[(3R)-1-(2- thienylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 158-168 0.003 372

3-[5-(2-{[(3R)-1- (phenylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 180-185 0.003 373

3-[5-(2-{[(3R)-1- (ethylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 162-170 >3 374

N-(4-{[(3R)-3-({4-[6-(3- hydraxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}phenyl)acetamide 180-192 0.001 375

3-{5-[2-({(3R)-1-[(2,2,2- trifluoroethyl)sulfonyl]piperidin-3-yl)amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol >300 >3376

3-{5-[2-({(3R)-1-[(1-methyl-1H- pyrazol-3-yl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl)phenol 196-2100.001 377

3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenylsulfamate 133-135 0.085 378

(4-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)methanol 136-137 2.26 379

4-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzamide177-179 2.67 380

3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]oxazol-6- yl}phenylsulfamate 142-145 1.59 381

3-[5-(2-{[(3R)-1-(4H-1,2,4-triazol- 3-ylsulfonyl)piperidin-3-yl]amino}pyrimidin-4- yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 218-2400.015 382

3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzoic acid190-195 1.19 383

3-(5-{2-[(3R)-piperidin-3- ylamino]pyrimidin-4-yl}imidazo[2,1-b][1,3]thiazol-6- yl)benzamide 202-205 3 384

1-(3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanone 124-127 1.3 385

4-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzaldehyde155-159 0.876 386

3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]oxazol-6- yl}phenylcarbamate 144-147 0.109 387

propyl 4-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1-carboxylate135-143 >3 388

3-[5-(2-{[(3R)-1-(2- thienylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6- yl]phenol 162-174 0.009 389

(1E)-1-(3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanone oxime 156-158 0.034 390

3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzaldehyde124-126 0.28 391

3-[5-(2-{[(3R)-1- (benzylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6- yl]phenol 222-227 >3 392

4-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzaldehydeoxime 174-177 0.698 393

3-[5-(2-{[(3R)-1- (propylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6- yl]phenol 144-155 0.33 394

methyl 4-({4-[6-(3- hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1-carboxylate275-280 >3 395

3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzaldehydeoxime 238-240 0.018 396

(3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)methanol 150-155 1.6 397

3-[5-(2-{[(3R)-1- (cyclopropylsulfonyl)piperidin-3-yl]amino}pyrimidin-4- yl)imidazo[2,1-b][1,3]oxazol-6- yl]phenol 163-1692.3 398

3-[5-(2-{[(3R)-1- (phenylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6- yl]phenol 152-157 0.042 399

3-[5-(2-{[(3R)-1-(3- thienylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6- yl]phenol 161-168 >3 400

1-(4-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanone 137-139 1.3

Other embodiments are within the following claims. While severalembodiments have been shown and described, various modifications may bemade without departing from the spirit and scope of the presentinvention.

1-33. (canceled)
 34. A compound of Formula II, or pharmaceuticallyacceptable salts thereof:

wherein X is O, S(O)_(p); m is an integer from 1 to 3; n is an integerfrom 1 to 3; p is an integer from 0 to 2; Z is hydrogen, a bond, —C(O)—,—C(O)NR₁₁—, —S(O)₂—, —C(O)NH—S(O)₂—, or CH(OH)—CH₂—Y—, wherein Y is CH₂,O, S, NH, or a bond; R₁ is halogen, —CN, —NO₂, —OH, —NR₆R₇, NR₈—C(O)R₉,—(CH₂)₀₋₃—C(O)NR₆R₇, —NR₈SO₂R₉, —NR₈C(O)NR₆R₇, —NR₈C(S)NR₆R₇,—OSO₂NR₅R₇, —C(N—OH)NH₂, —C(N—OH)R₈, —CH₂OR₈, —OC(O)NR₆R₇, —SR₉, or—C(O)NR₈SO₂R₉; R₂ is hydrogen, halogen, —CN, —NO₂, —OH, —NR₆R₇,NR₈—C(O)R₉, —(CH₂)₀₋₃—C(O)NR₆R₇, —NR₈SO₂R₉, —NR₈C(O)NR₆R₇,—NR₈C(S)NR₆R₇, —OSO₂NR₅R₇, —C(N—OH)NH₂, —C(N—OH)R₈, —CH₂OR₈,—OC(O)NR₆R₇, —SR₉, or —C(O)NR₈SO₂R₉, and R₁ and R₂, taken together, mayform a ring; R₃ and R₄ are independently hydrogen, substituted orunsubstituted, branched or unbranched (C₁-C₆)alkyl, —COOH, —COOR₈, or—C(O)NR₁₀R₁₁; each R₆ and each R₇ are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted heterocyclyl, and R₆ and R₇, takentogether, may form a ring; each R₈ is independently hydrogen, orsubstituted or unsubstituted, branched or unbranched (C₁-C₆)alkyl; eachR₉ is independently substituted or unsubstituted alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocyclyl, orsubstituted or unsubstituted heteroaryl; R₁₀ is substituted orunsubstituted, branched or unbranched (C₁-C₆)alkyl, or substituted orunsubstituted aryl; R₁₁ is hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted heteroaryl, and R₁₁, takentogether with R₁₀, may form a ring; R₁₂ is substituted or unsubstitutedalkyl, substituted or unsubstituted aryl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted heteroaryl; and R₁₃ isindependently selected from the group consisting of hydrogen, C₁-C₉alkyl, C₁-C₉ fluoro-substituted alkyl, C₃-C₈ cycloalkyl, C₃-C₈fluoro-substituted cycloalkyl, aryl, halogen-substituted aryl,heteroaryl, and halogen-substituted heteroaryl.
 35. The compound ofclaim 34 wherein R₃ and R₄ are hydrogen.
 36. The compound of claim 34wherein R₁₃ is hydrogen.
 37. The compound of claim 34 wherein m+n=4, ifm is not equal to n, then the preferred configuration is R.
 38. Thecompound of claim 34 wherein Z is —S(O)₂—.
 39. The compound of claim 34wherein m is an integer from 1 to 2; n is an integer from 1 to 2; Z is—C(O)—, —C(O)NR₁₁—, —S(O)₂—; and R³, R⁴ and R¹³ are hydrogen.
 40. Thecompound of claim 34 or 38 wherein, R₁₂ is a heteroaromatic group havingone, two or three aromatic rings containing from 1 to 4 heteroatoms inthe aromatic ring or a non-aromatic 3 to 7 membered monocyclicheterocyclic ring structure or 8 to 11 membered bicyclic heterocyclicring structure.
 41. A pharmaceutical composition comprising a compoundas defined in claim 34 or a pharmaceutically acceptable salt thereoftogether with one or more pharmaceutically acceptable carriers orexcipients.
 42. The pharmaceutical composition of claim 41 furthercomprising a second chemotherapeutic agent.
 43. The pharmaceuticalcomposition of claim 42, wherein said second chemotherapeutic agent isselected from the group consisting of tamoxifen, raloxifene,anastrozole, exemestane, letrozole, cisplatin, carboplatin, paclitaxel,cyclophosphamide, lovastatin, minosine, gemcitabine, araC,5-fluorouracil, methotrexate, docetaxel, goserelin, vincristin,vinblastin, nocodazole, teniposide, etoposide, epothilone, navelbine,camptothecin, daunonibicin, dactinomycin, mitoxantrone, amsacrine,doxorubicin, epirubicin, idarubicin imatanib, gefitinib, erlotinib,sorafenib, sunitinib malate, trastuzumab, rituximab, cetuximab, andbevacizumab.
 44. A method of treating a cell proliferative disorder,said method comprising administering to a subject having cells with saidcell proliferative disorder a therapeutically effective amount of acompound of formula II as claimed in claim 1, or a pharmaceuticallyacceptable salt thereof, or a prodrug or metabolite thereof, incombination with a pharmaceutically acceptable carrier, wherein saidcells with said cell proliferative disorder contain DNA encoding a RAF,and wherein said cell proliferative disorder is treated.
 45. The methodof claim 44 wherein R₃ and R₄ are hydrogen.
 46. The method of claim 44wherein R₁₃ is hydrogen.
 47. The method of claim 45 wherein m+n=4, if mis not equal to n, then the configuration is R.
 48. The method of claim45 wherein Z is —S(O)₂— and R₋₁₂ is 4-chlorophenyl, 4-fluorophenyl,4-cyanophenyl, methyl, or cyclopropyl.
 49. The method of claim 44wherein the compound is selected from the group consisting of3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenylcarbamate,3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenylsulfamate,3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenylsulfamate,3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenyl carbamate,(1E)-1-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanoneoxime,2-chloro-5-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenol,4-{[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfonyl}benzonitrile,4-{[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfonyl}benzoicacid,3-{[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfonyl}phenol,2-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzene-1,4-diol,3-[5-(2-{[(3R)-1-(methylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,3-{5-[2-({1-[(4-fluorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,3-{5-[2-({1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,N-ethyl-4-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxamide,3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,4-{[4-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfonyl}benzonitrile,4-{[4-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfonyl}benzamide,4-{[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfonyl}benzonitrile,3-{5-[2-({1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}-phenol,3-{5-[2-({1-[(4-fluorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenol,5-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}-2-fluorophenol,3-{5-[2-({(3R)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,3-[5-(2-{[(3R)-1-(3-thienylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,3-[5-(2-{[(3R)-1-(2-thienylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,3-[5-(2-{[(3R)-1-(phenylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,3-{5-[2-{(3R)-1-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,3-[5-(2-{[(3R)-1-(4H-1,2,4-triazol-3-ylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,3-[5-(2-{[(3R)-1-(2-thienylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol,3-[5-(2-{[(3R)-1-(phenylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol,3-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,3-[5-(2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,3-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol,3-[5-(2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol,5-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]-2-fluorophenol,and3-[5-(2-{[(3R)-1-(cyclopropylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol.50. The method of claim 44 wherein said cells with said cellproliferative disorder contain DNA encoding a RAF, and wherein the RAFis A-RAF, B-RAF, or C-RAF.
 51. The method of claim 50 wherein the RAF isB-RAF.
 52. The method of claim 51 wherein the B-RAF is selected from thegroup consisting of wild-type B-RAF, a B-RAF mutant and B-RAF^(V600E).53. The method of claim 44 wherein the cells have a constitutivelyenhanced RAF activity.
 54. The method of claim 44, wherein said compoundor a pharmaceutically acceptable salt thereof, or a prodrug ormetabolite thereof, is administered in combination with a secondchemotherapeutic agent.
 55. The method of claim 54, wherein said secondchemotherapeutic agent is selected from the group consisting oftamoxifen, raloxifene, anastrozole, exemestane, letrozole, cisplatin,carboplatin, paclitaxel, cyclophosphamide, lovastatin, minosine,gemcitabine, araC, 5-fluorouracil, methotrexate, docetaxel, goserelin,vincristin, vinblastin, nocodazole, teniposide, etoposide, epothilone,navelbine, camptothecin, daunonibicin, dactinomycin, mitoxantrone,amsacrine, doxorubicin, epirubicin, idarubicin imatanib, gefitinib,erlotinib, sorafenib, sunitinib malate, trastuzumab, rituximab,cetuximab, and bevacizumab.
 56. The use of claim 44 wherein said cellproliferative disorder is melanoma, a papillary thyroid cancer orCongenital Nevi.